CXCR4 Receptor Compounds

ABSTRACT

The invention relates generally to compounds which are allosteric modulators (e.g., positive and negative allosteric modulators, and allosteric agonists) of the G protein coupled receptor for stromal derived factor 1 (SDF-I), also known as the CX-CR4 receptor. The CXCR4 receptor compounds are derived from the intracellular loops and domains of the CXCR4 receptor. The invention also relates to the use of these CXCR4 receptor compounds and pharmaceutical compositions comprising the CXCR4 receptor compounds in the treatment of diseases and conditions associated with CXCR4 modulation such as bone marrow trans-plantation, chemosensitization, cancer, metastatic disease, inflammatory diseases, HIV infection and stem cell-based regenerative medicine.

RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No. 61/198,254, filed on Nov. 4, 2008 and U.S. Provisional Application No. 61/240,176, filed on Sep. 4, 2009. The entire teachings of the above applications are incorporated herein by reference.

BACKGROUND OF THE INVENTION

G protein coupled receptors (GPCRs) constitute one of the largest families of genes in the human genome. GPCRs are integral membrane signaling proteins. Hydrophobicity mapping of the amino acid sequences of G-protein coupled receptors has led to a model of the typical G-protein-coupled receptor as containing seven hydrophobic membrane-spanning regions with the amino terminal on the extracellular side of the membrane and the carboxyl terminal on the intracellular side of the membrane.

GPCRs mediate the transmission of intracellular signals (“signal transduction”) by activating guanine nucleotide-binding proteins (G proteins) to which the receptor is coupled. GPCRs are activated by a wide range of endogenous stimuli, including peptides, amino acids. hormones, light, and metal ions. The following reviews are incorporated by reference: Hill, British J. Pharm 147: s27 (2006); Palczeski, Ann Rev Biochemistry 75: 743-767 (2006); Dorsham & Gutkind, Nature Reviews 7: 79-94 (2007); Kobilka & Schertler, Trends Pharmacol Sci. 2: 79-83 (2008).

GPCRs are important targets for drug discovery as they are involved in a wide range of cellular signaling pathways and are implicated in many pathological conditions (e.g., cardiovascular and mental disorders, cancer, AIDS). In fact, GPCRs are targeted by 40-50% of approved drugs, illustrating the critical importance of this class of pharmaceutical targets. Interestingly, this number represents only about 30 GPCRs, a small fraction of the total number of GPCRs thought to be relevant to human disease. Over 1000 GPCRs are known in the human genome, and GPCRs remain challenging targets from a research and development perspective in part because these amembrane bound receptors with complex pharmacology.

There remains a need for the development of new pharmaceuticals that are allosteric modulators of GPCRs (e.g., negative and positive allosteric modulators, allosteric agonists, and ago-allosteric modulators).

SUMMARY OF THE INVENTION

The invention relates generally to compounds which are allosteric modulators (e.g., negative and positive allosteric modulators, allosteric agonists, and ago-allosteric modulators) of the G protein coupled receptor for stromal derived factor 1 (SDF-1, CXCL12), also known as the CXCR4 receptor. The CXCR4 receptor compounds are derived from the intracellular loops and domains of the CXCR4 receptor. The invention also relates to the use of these CXCR4 receptor compounds and pharmaceutical compositions comprising the CXCR4 receptor compounds in the treatment of diseases and conditions associated with CXCR4 receptor modulation such as bone marrow transplantation, chemosensitization, cancer, metastatic disease, inflammatory diseases, HIV infection and stem cell-based regenerative medicine.

-   -   More specifically, the invention relates to compounds         represented by Formula I:

TLP,

or a pharmaceutically acceptable salt thereof, wherein:

-   -   P is a peptide comprising at least three contiguous amino-acid         residues     -   of an intracellular i1, i2, i3 loop or an intracellular i4         domain of the CXCR4 receptor;     -   L is a linking moiety represented by C(O) and bonded to P at an         N terminal nitrogen of an N-terminal amino-acid residue;     -   and T is a lipophilic tether moiety bonded to L, wherein the         C-terminal amino acid residue of P is optionally functionalized.

The invention also relates to pharmaceutical compositions comprising one or more compounds of the invention and a carrier, and the use of the disclosed compounds and compositions in methods of treating diseases and conditions responsive to modulation (inhibition or activation) of the CXCR4 receptor.

BRIEF DESCRIPTION OF. THE DRAWINGS

The foregoing will be apparent from the following more particular description of example embodiments of the invention, as illustrated in the accompanying drawings in which like reference characters refer to the same parts throughout the different views. The drawings are not necessarily to scale, emphasis instead being placed upon illustrating embodiments of the present invention.

FIGS. 1A-1V are a series of graphical representations of compounds of the invention derived from the i1 loop in a chemotaxis assay as compared with vehicle.

FIGS. 2A-2D are a series of graphical representations of compounds of the invention derived from the i2 loop in a chemotaxis assay as compared with vehicle.

FIGS. 3A-3G are a series of graphical representations of compounds of the invention derived from the i3 loop in a chemotaxis assay as compared with vehicle.

FIGS. 4A-4D are a series of graphical representations of compounds of the invention derived from the i4 domain in a chemotaxis assay as compared with vehicle.

FIG. 5 is a graphical representation of SDF1-a dependent calcium mobilization in CEM cells upon testing with compounds of the invention.

FIG. 6 is a graphical representation of agonist activity of compounds of the invention in a CEM chemotaxis assay.

FIGS. 7A-7C is a series of graphs showing WBC mobilization of CXCR4 modulators in response to testing with compounds of the invention.

FIGS. 8A-8B is a series of graphs showing results of CXCR4 modulators in a PMN mobilization assay.

FIGS. 9A-9C is a series of graphs showing results of CXCR4 modulators in a lymphocyte mobilization assay.

FIG. 10 is a series of graphs showing the effects of CXCR-4 receptor compounds: 43, 88, 90 and 92 on burst forming unit-erythroid cells (BFU-E) and Colonly-forming unit granulocyte macrophages (CFU-GM).

FIG. 11 is a bar graph showing the effects of 10 μmmol/kg CXCR-4 receptor Compound No. 43 and AMD3100 on PMN recruitment in BALB/c mice following subcutaneous injection.

FIG. 12 is a bar graph showing the effects of 10 μmmol/kg CXCR-4 receptor Compound No. 43 and AMD3100 on lymphocyte recruitment in BALB/c mice following subcutaneous injection.

DETAILED DESCRIPTION OF THE INVENTION

A description of example embodiments of the invention follows.

G Protein Coupled Receptors (GPCRs)

G protein coupled receptors (GPCRs) constitute one of the largest superfamilies of genes in the human genome; these transmembrane proteins enable the cell the respond to its environment by sensing extracellular stimuli and initiating intracellular signal transduction cascades. GPCRs mediate signal transduction through the binding and activation of guanine nucleotide-binding proteins (G proteins) to which the receptor is coupled. Wide arrays of ligands bind to these receptors, which in turn orchestrate signaling networks integral to many cellular functions. Diverse GPCR ligands include small proteins, peptides, amino acids, biogenic amines, lipids, ions, odorants and even photons of light. The following reviews are incorporated by reference: Hill, British J. Pharm 147: s27 (2006); Dorsham & Gutkind, Nature Reviews 7: 79-94 (2007).

In addition to modulating a diverse array of homeostatic processes, GPCR signaling pathways are integral components of many pathological conditions (e.g., cardiovascular and mental disorders, cancer, AIDS). In fact, GPCRs are targeted by 40-50% of approved drugs illustrating the critical importance of this class of pharmaceutical targets. Interestingly, this number represents only about 30 GPCRs, a small fraction of the total number of GPCRs thought to be relevant to human disease. GPCRs are membrane bound receptors that exhibit complex pharmacological properties and remain challenging targets from a research and development perspective. Given their importance in human health combined with their prevalence (over 1000 known GPCRs in the human genome) GPCRs represent an important target receptor class for drug discovery and design.

GPCRs are integral membrane proteins that mediate diverse signaling cascades through an evolutionarily conserved structural motif. All GPCRs are thought to consist of seven hydrophobic transmembrane spanning α-helices with the amino terminus on the extracellular side of the membrane and the carboxyl terminus on the intracellular side of the membrane. The transmembrane helices are linked together sequentially by extracellular (e1, e2, e3) and intracellular (cytoplasmic) loops (i1, i2, i3). The intracellular loops or domains are intimately involved in the coupling and turnover of G proteins and include: i1, which connects TM1-TM2; i2, connecting TM3-TM4; i3, connecting TM5-TM6; and a portion of the C-terminal cytoplasmic tail (domain 4). Due in part to the topological homology of the 7TM domains and the recent high resolution crystal structures of several GPCRs (Palczewski et al., Science 289, 739-45 (2000), Rasmussen, S. G. et al., Nature 450, 383-7 (2007)) skilled modelers are now able to predict the general boundaries of GPCR loop domains through the alignment of several related receptors. These predictions are aided in part by a number of programs used by computational biologists, including EMBOSS, ClustalW2, Kalign, and MAFFT (Multiple Alignment using Fast Fourier Transform). Importantly, many of these programs are publically available (see, for example, The European Bioinformatics Institute (EMBL-EBI) web site http://www.ebi.ac.uk/Tools/) and most have web-based interfaces.

GPCR mediated signal transduction is initiated by the binding of a ligand to its cognate receptor. In many instances GPCR ligand binding is believed to take place in a hydrophilic pocket generated by a cluster of helices near the extracellular domain. However, other ligands, such as large peptides, are thought to bind to the extracellular region of protein and hydrophobic ligands are postulated to intercalate into a receptor binding pocket through the membrane between gaps in the helices. The process of ligand binding induces conformational changes within the receptor. These changes involve the outward movement of helix 6, which in turn alters the conformations of the intracellular loops and ultimately results in a receptor form that is able to bind and activate a heterotrimeric G protein (Farrens, D., et al. Science 274, 768-770 (1996), Gether, U. and Kobilka, B., J. Biol. Chem. 273, 17979-17982 (1998)). Upon binding the receptor catalyzes the exchange of GTP for GDP in the alpha subunit of the heterotrimeric G protein, which results in a separation of the G protein from the receptor as well a dissociation of the alpha and beta/gamma subunits of the G protein itself. Notably, this process is catalytic and results in signal amplification in that activation of one receptor may elicit the activation and turnover of numerous G proteins, which in turn may regulate multiple second messenger systems. Signaling diversity is further achieved through the existence of numerous G protein types as well as differing isoforms of alpha, beta and gamma subunits. Typically, GPCRs interact with G proteins to regulate the synthesis or inhibition of intracellular second messengers such as cyclic AMP, inositol phosphates, diacylglycerol and calcium ions, thereby triggering a cascade of intracellular events that eventually leads to a biological response.

GPCR signaling may be modulated and attenuated through cellular machinery as well as pharmacological intervention. Signal transduction may be ‘switched off’ with relatively fast kinetics (seconds to minutes) by a process called rapid desensitization. For GPCRs, this is caused by a functional uncoupling of receptors from heterotrimeric G proteins, without a detectable change in the total number of receptors present in cells or tissues. This process involves the phosphorylation of the receptor C terminus, which enables the protein arrestin to bind to the receptor and occlude further G protein coupling. Once bound by arrestin the receptor may be internalized into the cell and either recycled back to the cell surface or degraded. The alpha subunit of the G protein possesses intrisic GTPase activity, which attenuates signaling and promotes re-association with the beta/gamma subunits and a return to the basal state. GPCR signaling may also be modulated pharmacologically. Agonist drugs act directly to activate the receptors, whereas antagonist drugs act indirectly to block receptor signaling by preventing agonist activity through their associating with the receptor. GPCR binding and signaling can also be modified through allosteric modulation, that is by ligands that bind not at the orthosteric binding site but through binding at an allosteric site elsewhere in the receptors. Allosteric modulators can include both positive and negative modulators of orthosteric ligand mediated activity, allosteric agonists (that act in the absence of the orthosteric ligand), and ago-allosteric modulators (ligands that have agonist activity on their own but that can also modulate the activity of the orthosteric ligand).

The large superfamily of GPCRs may be divided into subclasses based on structural and functional similarities. GPCR families include Class A Rhodopsin like, Class B Secretin like, Class C Metabotropic glutamate/pheromone, Class D Fungal pheromone, Class E cAMP receptors (Dictyostelium), the Frizzled/Smoothened family, and various orphan GPCRs. In addition, putative families include Ocular albinism proteins, Insect odorant receptors, Plant Mlo receptors, Nematode chemoreceptors, Vomeronasal receptors (VIR & V3R) and taste receptors.

Class A GPCRs, also called family A or rhodopsin-like, are the largest class of receptors and characteristically have relatively small extracellular loops that form the basis for selectivity vs. endogenous agonists and small-molecule drugs. In addition, Class A receptors also have relatively small intracellular loops. Class A receptors include amine family members such as dopamine and serotonin, peptide members such as chemokine and opioid, the visual opsins, odorant receptors and an array of hormone receptors.

The CXCR4 receptor (SDF-1) is a Class A receptor that has been implicated in conditions such as cancer, metastatic disease, leukocyte homeostasis, hematopoietic stem cell homing to the bone marrow, hematopoietic cell engraftment, inflammatory diseases and HIV tropism.

Peptides

As defined herein, P is a peptide comprising at least three contiguous amino-acid residues (e.g., at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16) of an intracellular i1, i2 or i3 loop or intracellular i4 domain of the CXCR4 receptor. It is understood that, the N-terminal nitrogen of the N-terminal amino acid residue of P to which the linking moiety C(O) is bonded can be one of the at least three contiguous amino acid residues or it can be an amino acid residue distinct from the at least three contiguous amino acid residues.

Intracellular i1 loop as used herein refers to the loop which connects TM1 to TM2 and the corresponding transmembrane junctional residues.

Intracellular i2 loop as used herein refers to the loop which connects TM3 to TM4 and the corresponding transmembrane junctional residues.

Intracellular i3 loop as used herein refers to the loop which connects TM5 to TM6 and the corresponding transmembrane junctional residues.

Intracellular i4 domain as used herein refers to the C-terminal cytoplasmic tail and the transmembrane junctional residue.

In a specific embodiment, P comprises at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen contiguous amino acid residues of the intracellular i1, i2 or i3 loop or intracellular i4 domain of the CXCR4 receptor.

In certain embodiment, P is cyclized. The amino acids can be cyclized via their side chains or end to end.

In a more specific embodiment, the at least three contiguous amino acids of P (e.g., at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16) are derived from the intracellular i1, i2 or i3 loop or intracellular i4 domain of the CXCR4 receptor, wherein the amino acid sequence of each loop and the i4 domain is as described in Table 1.

TABLE 1 Intracellular Loop or Domain CXCR4 Receptor i1 MGYQKKLRSMTDKYRLH (SEQ ID NO: 370) i2 DRYLAIVHATNSQRPRKLLAEK (SEQ ID NO: 371) i3 IIISKLSHSKGHQKRKALKTTVI (SEQ ID NO: 372) i4 GAKFKTSAQHALTSVSRGSSLKILSKGKRGGH SSVSTESESSSFHSS (SEQ ID NO: 373)

It is understood that in addition to the amino acids listed in the sequences in Table 1, the intracellular loop for the i1 loop, i2 loop, i3 loop and i4 domain can also include the transmembrane junctional residues. For example, the i1 loop can include SEQ ID NO: 1 where one or more residues from the transmembrane junctional residues are included on either the C-terminus, the N-terminus or both. For example, SEQ ID NO: 1 can include either a Serine residue, or a Serine-Alanine residue at the C-terminus, SEQ ID NOS: 370 and 371 respectively. Similarly, the N-terminus of the i1 loop sequence described in Table 1 can also be extended to include a Valine residue (SEQ ID NO: 372) or -Valine-Leucine residues (SEQ ID NO: 373), or by -Valine-Leucine-Isoleucine residues (SEQ ID NO: 374) or by -Valine-Leucine-Isoleucine-Valine residues (SEQ ID NO 375).

In another embodiment, P comprises at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, or at least sixteen contiguous amino acid residues of the i1 intracellular loop of the CXCR4 receptor.

In an even more specific embodiment, P is selected from the group consisting of SEQ ID NOS:1-148 as listed in Table 2 below. Amino acids designated as lower case letters indicate D-amino acids.

TABLE 2  CXCR4 SEQ ID i-Loop Sequence NO: i1 SGYQKKLRSSTD 1 i1 MGYQKKLRSATD 2 i1 SGYQKKLRSMTD 3 i1 JGYQKKLRSJTD 4 i1 LGYQKKLRSLTD 5 i1 IGYQKKLRSITD 6 i1 JGYQKKLRSSTD 7 i1 JGYQKKLRSMTD 8 i1 LGYQKKLRSMTD 9 i1 IGYQKKLRSMTD 10 i1 AGYQKKLRSMTD 11 i1 MAYQKKLRSMTD 12 i1 MGAQKKLRSMTD 13 i1 MGYAKKLRSMTD 14 i1 MGYQKKLRAMTD 15 i1 MGYQKKLRSATD 16 i1 MGYQKKLRSMAD 17 i1 MGYQKKLRSMTA 18 i1 MGYQAKLRSMTD 19 i1 MGYQKKLASMTD 20 i1 MGYQKALRSMTD 21 i1 MGYQKKARSMTD 22 i1 mGYQKKLRSMTD 23 i1 MGyQKKLRSMTD 24 i1 MGYqKKLRSMTD 25 i1 MGYQkKLRSMTD 26 i1 MGYQKkLRSMTD 27 i1 MGYQKKlRSMTD 28 i1 MGYQKKLrSMTD 29 i1 MGYQKKLRsMTD 30 i1 MGYQKKLRSmTD 31 i1 MGYQKKLRSMtD 32 i1 MGYQKKLRSMTd 33 i1 GSHYQKKLRSSTD 34 i1 GSGYQKKLRSSTD 35 i1 YQKKLRSSTD 36 i1 GYQKKLRSJTD 37 i1 GYQKKLRSLTD 38 i1 GYQKKLRSMTDKYRLH 39 i1 YQKKLRSMTDKYRLH 40 i1 QKKLRSMTDKYRLH 41 i1 KKLRSMTDKYRLH 42 i1 KLRSMTDKYRLH 43 i1 LRSMTDKYRLH 44 i1 RSMTDKYRLH 45 i1 SMTDKYRLH 46 i1 MTDKYRLH 47 i1 TDKYRLH 48 i1 GYQKKLRSMTDKYRL 49 i1 GYQKKLRSMTDKYR 50 i1 GYQKKLRSMTDKY 51 i1 GYQKKLRSMTDK 52 i1 GYQKKLRSMTD 53 i1 GYQKKLRSITD- 54 i1 GYQKKLRSMT 55 i1 GYQKKLRSM 56 i1 GYQKKLRS 57 i1 GYQKKLR 58 i1 YQKKLRS 59 i1 QKKLRSM 60 i1 KKLRSMT 61 i1 KLRSMTD 62 i1 LRSMTDK 63 i1 RSMTDKY 64 i1 SMTDKYR 65 i1 MTDKYRL 66 i1 KRMKTSLYDGRMQYLK 67 i1 sGYQKKLRSSTD 68 i1 KKLRSMTDKY 69 i1 KKLRSMTDKYR 70 i1 KKLRSMTDKYRL 71 i1 KKLRSXTDKYRLH 72 (X = Norluceine (Nle)) i1 KKLRSMTDKYRLHL 73 i1 KKLRSMTDKYRLHLSV 74 i1 QKKLRSMTDKYRI 75 i1 QKKLRSMTDKYRLHL 76 i1 YQKKLRSMTDKYRLHLSV 77 i1 LVMGYQKKLRSMTD 78 i1 MGYQKKLRSMTDK 79 i1 MGYQKKLRSMTDKY 80 i1 MGYQKKLRSMTDKYRI 81 i1 MGYQKKLRSMTDKYRL 82 i1 MGYQKKLRSMTDKYRLHL 83 i1 MGYQKKLRSMTDKYRLHLSV 84 i1 YTKRLDSHRKLKM 85 i1 VMGYQKKLRSMTD 86 i1 KKLCRSMTDKCYRL 87 i1 KKLRCSMTDCKYRL 88 i1 kKLRSMTDKYRLH 89 i1 KkLRSMTDKYRLH 90 i1 KKlRSMTDKYRLH 91 i1 KKLrSMTDKYRLH 92 i1 KKLRsMTDKYRLH 93 i1 KKLRSmTDKYRLH 94 i1 AKLRSMTDKYRLH 95 i1 KALRSMTDKYRLH 96 i1 KKARSMTDKYRLH 97 i1 KKLASMTDKYRLH 98 i1 KKLRAMTDKYRLH 99 i1 KKLRSATDKYRLH 100 i1 AGYQKKLRSMTDKYRL 101 i1 MAYQKKLRSMTDKYRL 102 i1 MGAQKKLRSMTDKYRL 103 i1 MGYAKKLRSMTDKYRL 104 i1 MGYQAKLRSMTDKYRL 105 i1 MGYQKALRSMTDKYRL 106 i1 MGYQKKARSMTDKYRL 107 i1 MGYQKKLASMTDKYRL 108 i1 KKLRSMADKYRLH 109 i1 KKLRSMTAKYRLH 110 i1 KKLRSMTDAYRLH 111 i1 KKLRSMTDKARLH 112 i1 KKLRSMTDKYALH 113 i1 KKLRSMTDKYRAH 114 i1 KKLRSMTDKYRLA 115 i1 MGYQKKLRAMTDKYRL 116 i1 MGYQKKLRSATDKYRL 117 i1 MGYQKKLRSMADKYRL 118 i1 MGYQKKLRSMTAKYRL 119 i1 MGYQKKLRSMTDAYRL 120 i1 MGYQKKLRSMTDKARL 121 i1 MGYQKKLRSMTDKYAL 122 i1 MGYQKKLRSMTDKYRA 123 i1 KKLRSMtDKYRLH 124 i1 KKLRSMTdKYRLH 125 i1 KKLRSMTDKYrLH 126 i1 KKLRSMTDKYRlH 127 i1 KKLRSMTDKYRLh 128 i1 MGYQKKLRSMTDKYrL 129 i1 MGYQKKLRSMTDKyRL 130 i1 MGYQICKLRSMTDkYRL 131 i1 MGYQKKLRSMTdKYRL 132 i1 MGYQKKLRSMtDKYRL 133 i1 mGYQKKLRSMTDKYRL 134 i1 MGyQKKLRSMTDKYRL 135 i1 MGYqCKLRSMTDKYRL 136 i1 MGYQkKLRSMTDKYRL 137 i1 MGYQKkLRSMTDKYRL 138 i1 MGYQKKlRSMTDKYRL 139 i1 MGYQKKLrSMTDKYRL 140 i1 MGYQKKLRsMTDKYRL 141 i1 MGYQKKLRSmTDKYRL 142 i1 KKLRSMTDKYRlS 143 i1 MGYQKKLRSpTDKYRL 144 i1 MGYQKKLRpMTDKYRL 145 i1 MGYQKKLpSMTDKYRL 146 i1 MGYQKKpRSMTDKYRL 147 i1 MGYQKKLRSMPDKYRL 148

In another specific embodiment, the at least three contiguous amino acids of P (e.g., at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16) are derived from the i2 intracellular loop of the CXCR4 receptor.

In a more specific embodiment, P is selected from the group consisting of SEQ ID NOS: 149-199 as listed in Table 3 below.

TABLE 3  CXCR4 SEQ ID i-Loop Sequence NO: i2 DRYLAIVHATNSQRPRKLLAEK 149 i2 DRYLAIVHATNSQRPRKLLAE 150 i2 DRYLAIVHATNSQRPRKLLA 151 i2 DRYLAIVHATNSQRPRKLL 152 i2 DRYLAIVHATNSQRPRKL 153 i2 DRYLAIVHATNSQRPRK 154 i2 DRYLAIVHATNSQRPR 155 i2 DRYLAIVHATNSQRP 156 i2 DRYLAIVHATNSQR 157 i2 DRYLAIVHATNSQ 158 i2 DRYLAIVHATNS 159 i2 DRYLAIVHATN 160 i2 DRYLAIVHAT 161 i2 DRYLAIVHA 162 i2 DRYLAIVH 163 i2 DRYLAIV 164 i2 RYLAIVHATNSQRPRKLLAEK 165 i2 YLAIVHATNSQRPRKLLAEK 166 i2 LAIVHATNSQRPRKLLAEK 167 i2 AIVHATNSQRPRKLLAEK 168 i2 IVHATNSQRPRKLLAEK 169 i2 VHATNSQRPRKLLAEK 170 i2 HATNSQRPRKLLAEK- 171 i2 ATNSQRPRKLLAEK 172 i2 TNSQRPRKLLAEK 173 i2 NSQRPRKLLAEK 174 i2 SQRPRKLLAEK 175 i2 QRPRKLLAEK 176 i2 RPRKLLAEK 177 i2 PRKLLAEK 178 i2 RKLLAEK 179 i2 RYLAIVH- 180 i2 YLAIVHA 181 i2 LAIVHAT 182 i2 AIVHATN- 183 i2 IVHATNS- 184 i2 VHATNSQ 185 i2 HATNSQR 186 i2 ATNSQRP 187 i2 TNSQRPR- 188 i2 NSQRPRK 189 i2 SQRPRKL 190 i2 QRPRKLL 191 i2 RPRKLLA 192 i2 PRKLLAE 193 i2 VHATNSQRPRKLLAEKVVY 194 i2 VHATNSQRPRKLLA 195 i2 HATNSQRPRKL 196 i2 HATNSQRPRKLLA 197 i2 HATNSQRPRKLLAE 198 i2 HATNSQRPRKLLAEKV 199

In yet another specific embodiment, P comprises at least three contiguous amino (e.g., at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16) of the i3 intracellular loop of the CXCR4 receptor.

In a more specific embodiment, P is selected from the group consisting of SEQ ID NOS:200-254 as listed in Table 4 below.

TABLE 4  CXCR4 i-Loop Sequence SEQ ID: i3 HSKKGHQKRKALK 200 i3 JGYQKKLRSJTD 201 i3 IIISKLSHSKGHQKRKALKT 202 i3 IIISKLSHSKGHQKRKALK 203 i3 IIISKLSHSKGHQKRKAL 204 i3 IIISKLSHSKGHQKRKA 205 i3 IIISKLSHSKGHQKRK 206 i3 IIISKLSHSKGHQKR 207 i3 IIISKLSHSKGHQK 208 i3 IIISKLSHSKGHQ 209 i3 IIISKLSHSKGH 210 i3 IIISKLSHSKG 211 i3 IIISKLSHSK 212 i3 IIISKLSHS 213 i3 IIISKLSH 214 i3 IIISKLS 215 i3 IISKLSHSKGHQKRKALKT 216 i3 ISKLSHSKGHQKRKALKT 217 i3 SKLSHSKGHQKRKALKT 218 i3 KLSHSKGHQKRKALKT 219 i3 LSHSKGHQKRKALKT 220 i3 SHSKGHQKRKALKT 221 i3 HSKGHQKRKALKT 222 i3 SKGHQKRKALKT 223 i3 KGHQKRKALKT 224 i3 GHQKRKALKT 225 i3 HQKRKALKT 226 i3 QKRKALKT 227 i3 KRKALKT 228 i3 IISKLSH 229 i3 ISKLSHS 230 i3 SKLSHSK 231 i3 KLSHSKG 232 i3 LSHSKGH 233 i3 SHSKGHQ 234 i3 HSKGHQK 235 i3 SKGHQKR 236 i3 KGHQKRK 237 i3 GHQKRKA 238 i3 HQKRKAL 239 i3 QKRKALK 240 i3 HSKGHQKRKALKTT 241 i3 HSKGHQKRKALKTTV 242 i3 HSKGHQKRKALKTTVI 243 i3 HSKGHQKRKQALK 244 i3 KLSHSKGHQKRKA 245 i3 KLSHSKGHQKRKAL 246 i3 KLSHSKGHQKRKALK 247 i3 KLSHSKGHQKRKALKTTV 248 i3 KLSHSKGHQKRKALKTTVIL 249 i3 LSHSKGHQKRKALK 250 i3 SHSKGHQKRKALK 251 i3 SKLSHSKGHQKRKALK 252 i3 SKLSHSKGHQKRKALKTTVIL 253 i3 QHLHIALKKSTSRKVKSGTLK 254

In further specific embodiment, P comprises at least three contiguous amino (e.g., at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16) of the i4 intracellular domain of the CXCR4 receptor.

In a more specific embodiment, P is selected from the group consisting of SEQ ID NOS: 255-368 as listed in Table 5 below.

TABLE 5 CXCR4 SEQ ID i-Loop Sequence NO: i4 GAKFKTSAQHALTSVSRGSSLKILSKGKRGGHSSVSTESESSSFH 255 i4 GAKFKTSAQHALTSVSRGSSLKILSKGKRGGHSSVSTESESSSF 256 i4 GAKFKTSAQHALTSVSRGSSLKILSKGKRGGHSSVSTESESSS 257 i4 GAKFKTSAQHALTSVSRGSSLKILSKGKRGGHSSVSTESESS 258 i4 GAKFKTSAQHALTSVSRGSSLKILSKGKRGGHSSVSTESES 259 i4 GAKFKTSAQHALTSVSRGSSLKILSKGKRGGHSSVSTESE 260 i4 GAKFKTSAQHALTSVSRGSSLKILSKGKRGGHSSVSTES 261 i4 GAKFKTSAQHALTSVSRGSSLKILSKGKRGGHSSVSTE 262 i4 GAKFKTSAQHALTSVSRGSSLKILSKGKRGGHSSVST 263 i4 GAKFKTSAQHALTSVSRGSSLKILSKGKRGGHSSVS 264 i4 GAKFKTSAQHALTSVSRGSSLKILSKGKRGGHSSV 265 i4 GAKFKTSAQHALTSVSRGSSLKILSKGKRGGHSS 266 i4 GAKFKTSAQHALTSVSRGSSLKILSKGKRGGHS 267 i4 GAKFKTSAQHALTSVSRGSSLKILSKGKRGGH 268 i4 GAKFKTSAQHALTSVSRGSSLKILSKGKRGG 269 i4 GAKFKTSAQHALTSVSRGSSLKILSKGKRG 270 i4 GAKFKTSAQHALTSVSRGSSLKILSKGKR 271 i4 GAKFKTSAQHALTSVSRGSSLKILSKGK 272 i4 GAKFKTSAQHALTSVSRGSSLKILSKG 273 i4 GAKFKTSAQHALTSVSRGSSLKILSK 274 i4 GAKFKTSAQHALTSVSRGSSLKILS 275 i4 GAKFKTSAQHALTSVSRGSSLKIL 276 i4 GAKFKTSAQHALTSVSRGSSLKI 277 i4 GAKFKTSAQHALTSVSRGSSLK 278 i4 GAKFKTSAQHALTSVSRGSSL 279 i4 GAKFKTSAQHALTSVSRGSS 280 i4 GAKFKTSAQHALTSVSRGS 281 i4 GAKFKTSAQHALTSVSRG 282 i4 GAKFKTSAQHALTSVSR 283 i4 GAKFKTSAQHALTSVS 284 i4 GAKFKTSAQHALTSV 285 i4 GAKFKTSAQHALTS 286 i4 GAKFKTSAQHALT 287 i4 GAKFKTSAQHAL 288 i4 GAKFKTSAQHA 289 i4 GAKFKTSAQH 290 i4 AKFKTSAQHALTSVSRGSSLKILSKGKRGGHSSVSTESESSSFHSS 291 i4 KFKTSAQHALTSVSRGSSLKILSKGKRGGHSSVSTESESSSFHSS 292 i4 FKTSAQHALTSVSRGSSLKILSKGKRGGHSSVSTESESSSFHSS 293 i4 KTSAQHALTSVSRGSSLKILSKGKRGGHSSVSTESESSSFHSS 294 i4 TSAQHALTSVSRGSSLKILSKGKRGGHSSVSTESESSSFHSS 295 i4 SAQHALTSVSRGSSLKILSKGKRGGHSSVSTESESSSFHSS 296 i4 AQHALTSVSRGSSLKILSKGKRGGHSSVSTESESSSFHSS 297 i4 QHALTSVSRGSSLKILSKGKRGGHSSVSTESESSSFHSS 298 i4 HALTS VSRGSSLKILSKGKRGGHSSVSTESESSSFHSS 299 i4 ALTSVSRGSSLKILSKGKRGGHSSVSTESESSSFHSS 300 i4 LTSVSRGSSLKILSKGKRGGHSSVSTESESSSFHSS 301 i4 TSVSRGSSLKILSKGKRGGHSSVSTESESSSFHSS 302 i4 SVSRGSSLKILSKGKRGGHSSVSTESESSSFHSS 303 i4 VSRGSSLKILSKGKRGGHSSVSTESESSSFHSS 304 i4 SRGSSLKILSKGKRGGHSSVSTESESSSFHSS 305 i4 RGSSLKILSKGKRGGHSSVSTESESSSFHSS 306 i4 GSSLKILSKGKRGGHSSVSTESESSSFHSS 307 i4 SSLKILSKGKRGGHSSVSTESESSSFHSS 308 i4 SLKILSKGKRGGHSSVSTESESSSFHSS 309 i4 LKILSKGKRGGHSSVSTESESSSFHSS 310 i4 KILSKGKRGGHSSVSTESESSSFHSS 311 i4 ILSKGKRGGHSSVSTESESSSFHSS 312 i4 LSKGKRGGHSSVSTESESSSFHSS 313 i4 SKGKRGGHSSVSTESESSSFHSS 314 i4 KGKRGGHSSVSTESESSSFHSS 315 i4 GKRGGHSSVSTESESSSFHSS 316 i4 KRGGHSSVSTESESSSFHSS 317 i4 RGGHSSVSTESESSSFHSS 318 i4 GGHSSVSTESESSSFHSS 320 i4 GHSSVSTESESSSFHSS 321 i4 HSSVSTESESSSFHSS 322 i4 SSVSTESESSSFHSS 323 i4 SVSTESESSSFHSS 324 i4 VSTESESSSFHSS 325 i4 STESESSSFHSS 326 i4 TESESSSFHSS 327 i4 ESESSSFHSS 328 i4 AKFKTSAQHA 329 i4 KFKTSAQHAL 330 i4 FKTSAQHALT 331 i4 KTSAQHALTS 332 i4 TSAQHALTSV 333 i4 SAQHALTSVS 334 i4 AQHALTSVSR 335 i4 QHALTSVSRG 336 i4 HALTSVSRGS 337 i4 ALTSVSRGSS 338 i4 LTSVSRGSSL 339 i4 TSVSRGSSLK 340 i4 SVSRGSSLKI 341 i4 VSRGSSLKIL 342 i4 SRGSSLKILS 343 i4 RGSSLKILSK 345 i4 GSSLKILSKG 346 i4 SSLKILSKGK 347 i4 SLKILSKGKR 348 i4 LKILSKGKRG 349 i4 KILSKGKRGG 350 i4 ELSKGKRGGH 351 i4 LSKGKRGGHS 352 i4 SKGKRGGHSS 353 i4 KGKRGGHSSV 354 i4 GKRGGHSSVS 355 i4 KRGGHSSVST 356 i4 RGGHSSVSTE 357 i4 GGHSSVSTES 358 i4 GHSSVSTESE 359 i4 HSSVSTESES 360 i4 SSVSTESESS 361 i4 SVSTESESSS 362 i4 VSTESESSSF 363 i4 STESESSSFH 364 i4 TESESSSFHS 365 i4 ESESSSFHSS 366 i4 GAKFKTSAQHALTSVSRGSSLKILSKGKRGGHSSVSTESESSSFHS 367 i4 GAKFKTSAQHALTSVSRGSSLKILSKGKRGGHSCFH 368

It is understood that the sequences presented in Tables 2-5 can be optionally functionalized at the C-terminus. Functionalized at the C-terminus means that the acid moiety present at the C-terminus is replaced by some other functional group. Suitable functional groups include —C(O)N(R₂)₂, —C(O)OR₃, or C(O)NHC(O)OR₂, where R₂ is hydrogen or a an alkyl group, for example a (C₁-C₁₀) alkyl group and R₃ is an alkyl group, for example, a (C₁-C₁₀) alkyl group.

In another embodiment, the C-terminus of P has a lipophilic tether moiety. In certain embodiments, the lipophilic tether moiety is attached to a NH capped C-terminus of P.

It is understood that as long as P comprises the indicated number of contiguous amino acids residues from the CXCR4 intracellular loop (i1, i2 or i3) or domain (i4) from which it is derived, the remainder of the peptide, if present, can be selected from:

(a) any natural amino acid residue, unnatural amino acid residue or a combination thereof;

(b) a peptide sequence comprising natural amino acid residues, non-natural amino acid residues and combinations thereof;

(c) a peptide sequence according to (b) comprising one or more peptide backbone modifications;

(d) a peptide sequence according to (c) comprising one or more retro-inverso peptide linkages;

(e) a peptide sequence according to (c) wherein one or more peptide bonds are replaced by

or a combination thereof;

(f) a peptide sequence according to (c) comprising one or more depsipeptide linkages, wherein the amide linkage is replaced with an ester linkage; and

(g) a peptide sequence according to (c) comprising one or more conformational restrictions; and

(h) a peptide sequence according to (c) comprising one or more of (d)-(g).

Furthermore, it is understood that even within the indicated number of contiguous amino acid residues derived from the GPCR intracellular loop (i1, i2 or i3) or domain (i4), there can be: peptide backbone modifications such as, but not limited to, those described in (e) above; retro-inverso peptide linkages; despsipeptide linkages; conformational restrictions; or a combination thereof.

It is noted that P of Formula I can optionally functionalized at the C-terminus. Functionalized at the C-terminus means that the acid moiety present at the C-terminus is replaced by some other functional group. Suitable functional groups include —C(O)N(R₂)₂, —C(O)OR₃, or C(O)NHC(O)OR₂, where R₂ is hydrogen or an alkyl group, for example a (C₁-C₁₀) alkyl group and R₃ is an alkyl group, for example a (C₁-C₁₀) alkyl group. Functionalization of the C-terminus can result from the methods used to prepare.

Peptidomimetic as used herein refers to a compound comprising non-peptidic structural elements in place of a peptide sequence.

As used herein, the term “amino acid” includes both a naturally occurring amino acid and a non-natural amino acid.

As used herein, the term “naturally occurring amino acid” means a compound

represented by the formula NH₂—CHR—COOH, wherein R is the side chain of a naturally occurring amino acids such as lysine, arginine, serine, tyrosine etc. as shown in the Table below.

Table of Common Naturally Occurring Amino Acids Amino acid Three letter code One letter code Non-polar; alanine Ala A neutral at isoleucine Ile I pH 7.4 leucine Leu L methionine Met M phenylalanine Phe F proline Pro P tryptophan Trp W valine Val V Polar, asparagine Asn N uncharged cysteine Cys C at pH 7.0 glycine Gly G glutamine Gln Q serine Ser S threonine Thr T tyrosine Tyr Y Polar; glutamic acid Glu E charged at arginine Arg R pH 7 aspartic acid Asp D histidine His H lysine Lys K

“Non-natural amino acid” means an amino acid for which there is no nucleic acid codon. Examples of non-natural amino acids include, for example, the D-isomers of the natural α-amino acids such as D-proline (D-P, D-Pro) as indicated above; natural α-amino acids with non-natural side chains

related to phenylalanine); Aib (aminobutyric acid), bAib (3-aminoisobutyric acid), Nva (norvaline), β-Ala, Aad (2-aminoadipic acid), bAad (3-aminoadipic acid), Abu (2-aminobutyric acid), Gaba (γ-aminobutyric acid), Acp (6-aminocaproic acid), Dbu (2,4-diaminobutryic acid), α-aminopimelic acid, TMSA (trimethylsilyl-Ala), aIle (allo-isoleucine), Nle (norleucine), tert-Leu, Cit (citrulline), Orn (ornithine, O), Dpm (2,2′-diaminopimelic acid), Dpr (2,3-diaminopropionic acid), α or β-Nal, Cha (cyclohexyl-Ala), hydroxyproline, Sar (sarcosine), and the like.

Unnatural amino acids also include cyclic amino acids; and amino acid analogs, for example, N^(α)-alkylated amino acids such as MeGly (N^(α)-methylglycine), EtGly (N^(α)-ethylglycine) and EtAsn (N^(α)-ethylasparagine); and amino acids in which the α-carbon bears two side-chain substituents. As with the natural amino acids, the residues of the unnatural amino acids are what are left behind when the unnatural amino acid becomes part of a peptide sequence as described herein.

Amino acid residues are amino acid structures as described above that lack a hydrogen atom of the amino group or the hydroxyl moiety of the carboxyl group or both resulting in the units of a peptide chain being amino-acid residues.

The D-isomers of the natural amino acids are designated herein with a lower case letter of the corresponding naturally occurring amino acid. For example, d-proline is designated “p” rather than “P” as is used for naturally occurring proline.

Tethers (T)

T of Formula I is a lipohilic tether moiety which imparts lipophilicity to the CXCR4 receptor compounds of the invention. The lipophilicity which T imparts, can promote penetration of the CXCR4 receptor compounds into the cell membrane and tethering of the CXCR4 receptor compounds to the cell membrane. As such, the lipophilicity imparted by T can facilitate interaction between the CXCR4 receptor compounds of the invention and the cognate receptor.

The relative lipophilicity of compounds suitable for use as the lipophilic tether moiety of Formula I can be quantified by measuring the amount of the compound that partitions into an organic solvent layer (membrane-like) vs. an aqueous solvent layer (analogous to the extracellular or cytoplasmic environment). The partition coefficient in a mixed solvent composition, such as octanol/water or octanol/PBS, is the ratio of compound found at equilibrium in the octanol vs. the aqueous solvent (Partition coeff P=[compound]_(octanol)/[compound]_(aqueous)). Frequently, the partition coefficient is expressed in logarithmic form, as the log P. Compounds with greater lipophilicity have a more positive log P than more hydrophilic compounds and tend to interact more strongly with membrane bilayers.

Computational programs are also available for calculating the partition coefficient for compounds suitable for use as the lipophilic tether moiety (T). In situations where the chemical structure is being varied in a systematic manner, for example by adding additional methylene units (—CH₂—) onto to an existing alkyl group, the trend in log P can be calculated using, for example, ChemDraw (CambridgeSoft, Inc).

In one embodiment, T is an optionally substituted (C₆-C₃₀)alkyl, (C₆-C₃₀)alkenyl, (C₆-C₃₀)alkynyl wherein 0-3 carbon atoms are replaced with oxygen, sulfur, nitrogen or a combination thereof.

In a specific embodiment, the (C₆-C₃₀)alkyl, (C₆-C₃₀)alkenyl, (C₆-C₃₀)alkynyl are substituted at one or more substitutable carbon atoms with halogen, —CN, —OH, —NH₂, NO₂, —NH(C₁-C₆)alkyl, —N((C₁-C₆)alkyl)₂, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, (C₁-C₆)alkoxy, (C₁-C₆)haloalkoxy, aryloxy, (C₁-C₆)alkoxycarbonyl, —CONH₂, —OCONH₂, —NHCONH₂, —N(C₁-C₆)alkylCONH₂, —N(C₁-C₆)alkylCONH(C₁-C₆)alkyl, —NHCONH(C₁-C₆)alkyl, —NHCON((C₁-C₆)alkyl)₂, —N(C₁-C₆)alkylCON((C₁-C₆)alkyl)₂, —NHC(S)NH₂, —N(C₁-C₆)alkylC(S)NH₂, —N(C₁-C₆)alkylC(S)NH(C₁-C₆)alkyl, —NHC(S)NH(C₁-C₆)alkyl, —NHC(S)N((C₁-C₆)alkyl)₂, —N(C₁-C₆)alkylC(S)N((C₁-C₆)alkyl)₂, —CONH(C₁-C₆)alkyl, —OCONH(C₁-C₆)alkyl —CON((C₁-C₆)alkyl)₂, —C(S)(C₁-C₆)alkyl, —S(O)_(p)(C₁-C₆)alkyl, —S(O)_(p)NH₂, —S(O)_(p)NH(C₁-C₆)alkyl, —S(O)_(p)N((C₁-C₆)alkyl)₂, —CO(C₁-C₆)alkyl, —OCO(C₁-C₆)alkyl, —C(O)O(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —C(O)H or —CO₂H; and p is 1 or 2.

In a specific embodiment, T is selected from the group consisting of: CH₃(CH₂)₉OPh-, CH₃(CH₂)₆C═C(CH₂)₆, CH₃(CH₂)₁₁O(CH₂)₃, CH₃(CH₂)₉O(CH₂)₂ and CH₃(CH₂)₁₃.

In a specific embodiment, T is selected from the group consisting of: CH₃(CH₂)₁₆, CH₃(CH₂)₁₅, CH₃(CH₂)₁₄, CH₃(CH₂)₁₃, CH₃(CH₂)₁₂, CH₃(CH₂)₁₁, CH₃(CH₂)₁₀, CH₃(CH₂)₉, CH₃(CH₂)₈, CH₃(CH₂)₉OPh-, CH₃(CH₂)₆C↑C(CH₂)₆, CH₃(CH₂)₁₁O(CH₂)₃, and CH₃(CH₂)₉O(CH₂)₂ and CH₃(CH₂)₁₃.

It is understood that the lipophilic moiety (T) of Formula I can be derived from precursor liphophilic compounds (e.g., fatty acids and bile acids). As used herein, “derived from” with regard to T, means that T is derived from a precursor lipophilic compound and that reaction of the precursor lipophilic compound in preparing the APJ receptor compounds of Formula I, results in a lipophilic tether moiety represented by T in Formula I that is structurally modified in comparison to the precursor lipophilic compound.

For example, the lipophilic tether moiety, T of Formula I, can be derived from a fatty acid or a bile acid. It is understood that in accordance with Formula I, when T is derived from a fatty acid (i.e., a fatty acid derivative) it is attached to L-P at the carbon atom alpha to the carbonyl carbon of the acid functional group in the fatty acid from which it is derived. For example, when T is derived from palmitic acid

T of Formula I has the following structure:

Similarly, when T is derived from stearic acid,

T of Formula I has the following structure:

Similarly when T is derived from 3-(dodecyloxy)propanoic acid,

T of Formula I has the following structure:

Similarly, when T is derived from 4-(undecyloxy)butanoic acid,

T of Formula I has the following structure:

Similarly, when T is derived from elaidic acid,

T of Formula I has the following structure:

Similarly, when T is derived from oleic acid,

T of Formula I has the following structure:

Similarly, when T is derived from 16-hydroxypalmitic acid,

T of Formula I has the following structure:

Similarly, when T is derived from 2-aminooctadecanoic acid

T of Formula I has the following structure:

Similarly, when T is derived from 2-amino-4-(dodecyloxy)butanoic acid

T of Formula I has the following structure:

In a further embodiment, T is derived from a fatty acid. In a specific embodiment, T is derived from a fatty acid selected from the group consisting of: butyric acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, and lignoceric acid.

In another specific embodiment, T is derived from a fatty acid selected from the group consisting of: myristoleic acid, palmitoleic acid, oleic acid, linoleic acid, α-linolenic acid, arachidonic acid, eicosapentaenoic acid, erucic acid, docosahexaenoic acid.

In another embodiment, T of Formula I can be derived from a bile acid. Similar to the embodiment where T is a fatty acid derivative, it is understood that in accordance with Formula I, when T is derived from a bile acid (i.e., a bile acid derivative) it is attached to L-P at the carbon atom alpha to the carbonyl carbon of the acid functional group in the bile acid from which it is derived. For example, when T is derived from lithocholic acid,

T of Formula I has the following structure:

In a further embodiment, T is derived from a bile acid. In a specific embodiment, T is derived from a bile acid selected from the group consisting of: lithocholic acid, chenodeoxycholic acid, deoxycholic acid, cholanic acid, cholic acid, ursocholic acid, ursodeoxycholic acid, isoursodeoxycholic acid, lagodeoxycholic acid, dehydrocholic acid, hyocholic acid, hyodeoxycholic acid and the like.

For example, T is selected from:

In another further embodiment, T is derived from a bile acid described above that has been modified at other than the acid functional group. For example, T can be derived from any of the bile acids described above, where the hydroxy position has been modified to form an ester or a halo ester. For example, T can be:

Other lipophilic moieties suitable for use as the lipophilic membrane tether, T, of Formula I, include but are not limited to steroids. Suitable steroids include, but are not limited to, sterols; progestagens; glucocorticoids; mineralcorticoids; androgens; and estrogens. Generally any steroid capable of attachment or which can be modified for incorporation into Formula I can be used. It is understood that the lipophilic membrane tether, T, may be slightly modified from the precursor lipophilic compound as a result of incorporation into Formula I.

Suitable sterols for use in the invention at T, include but are not limited to: cholestanol, coprostanol, cholesterol, epicholesterol, ergosterol, ergocalciferol, and the like. Preferred sterols are those that provide a balance of lipophilicity with water solubility.

Suitable progestagens include, but are not limited to progesterone. Suitable glucocorticoids include, but are not limited to cortisol. Suitable mineralcorticoids include, but are not limited to aldosterone. Suitable androgens include, but are not limited to testosterone and androstenedione. Suitable estrogens include, but are not limited to estrone and estradiol.

In another specific embodiment, T can be derived from 2-tetradecanamideooctadecanoid acid. Similar to the embodiment where T is a fatty acid derivative, it is understood that in accordance with Formula I, when T is derived from 2-tetradecanamideooctadecanoid acid it is attached to L-P at the carbon atom alpha to the carbonyl carbon of the acid functional group in the bile acid from which it is derived. For example, when T is derived from 2-tetradecanamideooctadecanoid acid, the tether is:

In another embodiment, T of Formula I can be derived from 2-(5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido)octadecanoic acid. For example, when T is derived from 2-(5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido)octadecanoic acid, the tether is:

In yet another embodiment, T of Formula I can be:

It is understood, that the compounds can contain one of more tether moieties. In certain aspects, the tether moieties are the same. In other embodiments, the tether moieties are different.

Compounds (T-L-P)

In a first aspect, the GPCR Compound of the invention is represented by Formula I:

T-L-P,

or a pharmaceutically acceptable salt thereof, wherein:

-   -   P is a peptide comprising at least three contiguous amino-acid         residues     -   of an intracellular i1, i2, i3 loop or an intracellular i4         domain of the CXCR4 receptor;     -   L is a linking moiety represented by C(O) and bonded to P at an         N terminal nitrogen of an N-terminal amino-acid residue;     -   and T is a lipophilic tether moiety bonded to L, wherein the         C-terminal amino acid residue of P is optionally functionalized.         In a second aspect, P comprises at least six contiguous amino         acid residues.

In a third aspect, P comprises at least 3 contiguous amino acids of the i1 loop.

In a specific embodiment of the third aspect, the i1 loop of the CXCR4 receptor from which P is derived has the following sequence:

(SEQ ID NO: 370) MGYQKKLRSMTDKYRLH.

In another embodiment of the third aspect, P is a sequence selected from:

CXCR4 SEQ ID i-Loop Sequence NO: i1 SGYQKKLRSSTD 1 i1 MGYQKKLRSSTD 2 i1 SGYQKKLRSMTD 3 i1 JGYQKKLRSJTD 4 i1 LGYQKKLRSLTD 5 i1 IGYQKKLRSITD 6 i1 JGYQKKLRSSTD 7 i1 JGYQKKLRSMTD 8 i1 LGYQKKLRSMTD 9 i1 IGYQKKLRSMTD 10 i1 AGYQKKLRSMTD 11 i1 MAYQKKLRSMTD 12 i1 MGAQKKLRSMTD 13 i1 MGYAKKLRSMTD 14 i1 MGYQKKLRAMTD 15 i1 MGYQKKLRSATD 16 i1 MGYQKKLRSMAD 17 i1 MGYQKKLRSMTA 18 i1 MGYQAKLRSMTD 19 i1 MGYQKKLASMTD 20 i1 MGYQKALRSMTD 21 i1 MGYQKKARSMTD 22 i1 mGYQKKLRSMTD 23 i1 MGyQKKLRSMTD 24 i1 MGYqKKLRSMTD 25 i1 MGYQkKLRSMTD 26 i1 MGYQKkLRSMTD 27 i1 MGYQKKlRSMTD 28 i1 MGYQKKLrSMTD 29 i1 MGYQKKLRsMTD 30 i1 MGYQKKLRSmTD 31 i1 MGYQKKLRSMtD 32 i1 MGYQKKLRSMTd 33 i1 GSHYQKKLRSSTD 34 i1 GSGYQKKLRSSTD 35 i1 YQKKLRSSTD 36 i1 GYQKKLRSJTD 37 i1 GYQKKLRSLTD 38 i1 GYQKKLRSMTDKYRLH 39 i1 YQKKLRSMTDKYRLH 40 i1 QKKLRSMTDKYRLH 41 i1 KKLRSMTDKYRLH 42 i1 KLRSMTDKYRLH 43 i1 LRSMTDKYRLH 44 i1 RSMTDKYRLH 45 i1 SMTDKYRLH 46 i1 MTDKYRLH 47 i1 TDKYRLH 48 i1 GYQKKLRSMTDKYRL 49 i1 GYQKKLRSMTDKYR 50 i1 GYQKKLRSMTDKY 51 i1 GYQKKLRSMTDK 52 i1 GYQKKLRSMTD 53 i1 GYQKKLRSITD- 54 i1 GYQKKLRSMT 55 i1 GYQKKLRSM 56 i1 GYQKKLRS 57 i1 GYQKKLR 58 i1 YQKKLRS 59 i1 QKKLRSM 60 i1 KKLRSMT 61 i1 KLRSMTD 62 i1 LRSMTDK 63 i1 RSMTDKY 64 i1 SMTDKYR 65 i1 MTDKYRL 66 i1 KRMKTSLYDGRMQYLK 67 i1 sGYQKKLRSSTD 68 i1 KKLRSMTDKY 69 i1 KKLRSMTDKYR 70 i1 KKLRSMTDKYRL 71 i1 KKLRSXTDKYRLH 72 (X = Norluceine (Nle)) i1 KKLRSMTDKYRLHL 73 i1 KKLRSMTDKYRLHLSV 74 i1 QKKLRSMTDKYRI 75 i1 QKKLRSMTDKYRLHL 76 i1 YQKKLRSMTDKYRLHLSV 77 i1 LVMGYQKKLRSMTD 78 i1 MGYQKKLRSMTDK 79 i1 MGYQKKLRSMTDKY 80 i1 MGYQKKLRSMTDKYRI 81 i1 MGYQKKLRSMTDKYRL 82 i1 MGYQKKLRSMTDKYRLHL 83 i1 MGYQKKLRSMTDKYRLHLSV 84 i1 YTKRLDSHRKLKM 85 i1 VMGYQKKLRSMTD 86 i1 KKLCRSMTDKCYRL 87 i1 KKLRCSMTDCKYRL 88 i1 kKLRSMTDKYRLH 89 i1 KkLRSMTDKYRLH 90 i1 KKIRSMTDKYRLH 91 i1 KKLrSMTDKYRLH 92 i1 KKLRsMTDKYRLH 93 i1 KKLRSmTDKYRLH 94 i1 AKLRSMTDKYRLH 95 i1 KALRSMTDKYRLH 96 i1 KKARSMTDKYRLH 97 i1 KKLASMTDKYRLH 98 i1 KKLRAMTDKYRLH 99 i1 KKLRSATDKYRLH 100 i1 AGYQKKLRSMTDKYRL 101 i1 MAYQKKLRSMTDKYRL 102 i1 MGAQKKLRSMTDKYRL 103 i1 MGYAKKLRSMTDKYRL 104 i1 MGYQAKLRSMTDKYRL 105 i1 MGYQKALRSMTDKYRL 106 i1 MGYQKKARSMTDKYRL 107 i1 MGYQKKLASMTDKYRL 108 i1 KKLRSMADKYRLH 109 i1 KKLRSMTAKYRLH 110 i1 KKLRSMTDAYRLH 111 i1 KKLRSMTDKARLH 112 i1 KKLRSMTDKYALH 113 i1 KKLRSMTDKYRAH 114 i1 KKLRSMTDKYRLA 115 i1 MGYQKKLRAMTDKYRL 116 i1 MGYQKKLRSATDKYRL 117 i1 MGYQKKLRSMADKYRL 118 i1 MGYQKKLRSMTAKYRL 119 i1 MGYQKKLRSMTDAYRL 120 i1 MGYQKKLRSMTDKARL 121 i1 MGYQKKLRSMTDKYAL 122 i1 MGYQKKLRSMTDKYRA 123 i1 KKLRSMtDKYRLH 124 i1 KKLRSMTdKYRLH 125 i1 KKLRSMTDKYrLH 126 i1 KKLRSMTDKYRlH 127 i1 KKLRSMTDKYRLh 128 i1 MGYQKKLRSMTDKYrL 129 i1 MGYQKKLRSMTDKyRL 130 i1 MGYQKKLRSMTDkYRL 131 i1 MGYQKKLRSMTdKYRL 132 i1 MGYQKKLRSMtDKYRL 133 i1 mGYQKKLRSMTDKYRL 134 i1 MGyQKKLRSMTDKYRL 135 i1 MGYqKKLRSMTDKYRL 136 i1 MGYQkKLRSMTDKYRL 137 i1 MGYQKkLRSMTDKYRL 138 i1 MGYQKKpRSMTDKYRL 139 i1 MGYQKKLrSMTDKYRL 140 i1 MGYQKKLRsMTDKYRL 141 i1 MGYQKKLRSmTDKYRL 142 i1 KKLRSMTDKYRlS 143 i1 MGYQKKLRSpTDKYRL 144 i1 MGYQKKLRpMTDKYRL 145 i1 MGYQKKLpSMTDKYRL 146 i1 MGYQKKpRSMTDKYRL 147 i1 MGYQKKLRSMPDKYRL 148

It is understood that for the embodiments presented herein, that when the amino acid residues of P are represented by X, W, Y or Z that the C-terminal amino acid residue does not include the —OH of the amino acid and that the end group R1 that is bonded to the C-terminal residue includes —OH as well as other moieties defined herein.

In a more specific embodiment, the compounds is represented by Formula A:

-   -   T-L-X₁-X₂-X₃-X₄-X₅-X₆-X₇-X₈-X₉-X₁₀-X₁₁-X₁₂-X₁₃-X₁₄-X₁₅-X₁₆-X₁₇-X₁₈-X₁₉-X₂₀-X₂₁-X₂₂-X₂₃-X₂₄-R₁;         or a pharmaceutically acceptable salt thereof, wherein: L is a         linking moiety represented by C(O) and bonded to the N terminal         nitrogen of X₁ or the next present amino acid residue if X₁ is         absent; T is a lipophilic tether moiety bonded to L; and R₁ is         OR₂ or N(R₂)₂, each R₂ is independently H or alkyl,     -   wherein at least three contiguous X₁-X₂₄ amino acid residues are         present, and wherein:     -   X₁ is a valine residue or absent     -   X₂ is a isoleucine residue or absent,     -   X₃ is a leucine residue or absent,     -   X₄ is a valine residue, a glycine residue or absent,     -   X₅ is a methionine residue, a isoleucine residue, a leucine         residue, a norleucine residue, a serine residue, an alanine         residue, a d-methionine residue, a d-serine residue, or absent,     -   X₆ is a glycine residue, an alanine residue, a histidine         residue, a lysine residue or absent,     -   X₇ is a tyrosine residue, an alanine residue, a d-tyrosine         residue, an arginine residue or absent     -   X₈ is a glutamine residue, an alanine residue, a d-glutamine         residue, a methionine residue, a threonine residue, or a lysine         residue or absent,     -   X₉ is a lysine residue, a d-lysine residue, a alanine residue or         absent,     -   X₁₀ is a lysine residue, a d-lysine residue, a leucine residue,         a threonine residue, an alanine residue or absent,     -   X₁₁ is a leucine residue, a d-leucine residue, an alanine         residue, an isoleucine residue, a serine residue, a cysteine         residue, an arginine residue or absent,     -   X₁₂ is an arginine residue, a d-arginine residue, an alanine         residue, a leucine residue, an aspartic acid residue, a cysteine         residue, or absent,     -   X₁₃ is a serine residue, a d-serine residue, an alanine residue,         a tyrosine residue or absent,     -   X₁₄ is a methionine residue, a serine residue, a leucine         residue, an isoleucine residue, a norleucine residue, an alanine         residue, a d-methionine residue, an aspartic acid residue, or         absent,     -   X₁₅ is a threonine residue, a d-threonine residue, a arginine         residue, a glycine residue, an alanine residue or absent,     -   X₁₆ is an aspartic acid residue, and -aspartic acid residue, an         alanine residue, an arginine residue, a lysine residue or         absent,     -   X₁₇ is a methionine residue, a lysine residue, a histidine         residue, a leucine residue, a cysteine residue or absent,     -   X₁₈ is a tyrosine residue, a glutamine residue, a leucine         residue, a lysine residue, a cysteine residue or absent,     -   X₁₉ is an arginine residue, a tyrosine residue, a serine         residue, a methionine residue or absent,     -   X₂₀ is a leucine residue, a isoleucine residue, an arginine         residue, or a valine residue or absent,     -   X₂₁ is a histidine residue, a lysine residue, a leucine residue         or absent,     -   X₂₂ is a leucine residue, a tyrosine residue or absent,     -   X₂₃ is an arginine residue, a serine residue or absent, and     -   X₂₄ is a valine residue, a leucine residue or absent;         wherein when X₁-X₄ and X₁₇-X₂₄ are absent and X₅ is a methionine         residue, then at least one of the amino acids of X₆-X₁₆ is an         alanine residue or a d-amino acid, and wherein when X₁-X₆ and         X₁₇-X₂₄ are absent and X₇ is a tyrosine residue then at least         one of the amino acids of X₈-X₁₆ is an alanine residue, d-amino         acid or a serine residue.

In another aspect, the compound is represented wherein, X₁-X₄ and X₁₇-X₂₄ are absent and

wherein:

-   -   X₅ is a methionine residue, a d-methionine residue, an         isoleucine residue, a leucine residue, a serine residue, an         alanine residue, or d-a methionine residue,     -   X₆ is a glycine residue or an alanine residue,     -   X₇ is a tyrosine residue, an alanine residue, or a d-tyrosine         residue,     -   X₈ is a glutamine residue, an alanine residue or a d-glutamine         residue,     -   X₉ is a lysine residue, a d-lysine residue, or an alanine         residue,     -   X₁₀ is a lysine residue, a d-lysine residue, or an alanine         residue,     -   X₁₁ is a leucine residue, a d-leucine residue, or an alanine         residue,     -   X₁₂ is an arginine residue, a d-arginine residue, or an alanine         residue,     -   X₁₃ is a serine residue, a d-serine residue, or an alanine         residue,     -   X₁₄ is a methionine residue, a serine residue, a leucine         residue, an isoleucine residue, an alanine residue, or a         d-methionine residue,     -   X₁₅ is a threonine residue, a d-threonine residue, or an alanine         residue, and     -   X₁₆ is aspartic acid residue, a d-aspartic acid residue, or an         alanine residue, or an arginine residue.

In yet another aspect, when X, —X₄ and X₂₁-X₂₄ are absent, and wherein:

-   -   X₅ is a methionine residue, a d-methionine residue an alanine         residue or a glycine residue,     -   X₆ is a glycine residue or an alanine residue,     -   X₇ is a tyrosine residue, a d-tyrosine residue, or an alanine         residue,     -   X₈ is a glutamine residue, d-glutamine residue, or an alanine         residue,     -   X₉ is a lysine residue, a d-lysine residue or an alanine         residue,     -   X₁₀ is a lysine residue, a d-lysine residue or an alanine         residue,     -   X₁₁ is a leucine residue, a d-leucine residue, an alanine         residue, a proline residue or a d-proline residue,     -   X₁₂ is an arginine residue, a d-arginine residue, an alanine         residue, a proline residue or d-proline residue,     -   X₁₃ is a serine residue, a d-serine residue, an alanine residue,         a proline residue or a d-proline residue,     -   X₁₄ is a methionine residue, an alanine residue, a d-methionine         residue, a d-proline residue, a glycine residue, a histidine         residue, or noreleucine residue     -   X₁₅ is a threonine residue, a d-threonine residue, a d-proline         residue, a proline residue or an alanine residue,     -   X₁₆ is an aspartic acid residue, a d-aspartic acid residue, or         an alanine residue,     -   X₁₇ is a lysine residue, a d-lysine residue or an alanine         residue,     -   X₁₈ is a tyrosine residue, a d-tyrosine residue, or an alanine         residue,     -   X₁₉ is an arginine residue, a lysine residue, or a d-arginine         residue, and     -   X₂₀ is a leucine residue, a d-leucine residue, an alanine         residue, a noreleucine residue, an isoleucine residue or a         valine residue.

In another aspect, when X₁-X₈ are absent, and wherein:

-   -   X₉ is a lysine residue, a d-lysine residue or an alanine         residue,     -   X₁₀ is a lysine residue, a d-lysine residue or an alanine         residue,     -   X₁₁ is a leucine residue, a d-leucine residue or an alanine         residue,     -   X₁₂ is an arginine residue, a d-arginine residue or an alanine         residue,     -   X₁₃ is a serine residue, a d-serine residue or an alanine         residue,     -   X₁₄ is a methionine residue, a d-methionine residue, a         norleucine residue or an alanine residue,     -   X₁₅ is a threonine residue, a d-threonine residue, or an alanine         residue,     -   X₁₆ is an aspartic acid residue, a d-aspartic acid residue, or         an alanine residue,     -   X₁₇ is a lysine residue, a d-lysine residue or an alanine         residue,     -   X₁₈ is a tyrosine residue, a d-tyrosine residue, an alanine         residue or absent,     -   X₁₉ is an arginine residue, a d-arginine, an alanine residue or         absent,     -   X₂₀ is leucine residue, a d-leucine, an alanine or absent,     -   X₂₁ is a histidine residue, a d-histidine residue, a d-serine         residue, an alanine residue or absent,     -   X₂₂ is leucine residue, isoleucine residue or absent,     -   X₂₃ is a serine residue or absent, and     -   X₂₄ is a valine residue or absent. In another embodiment, X₂₂,         X₂₃ and X₂₄ are absent.

In yet another specific aspect, X₁-X₅ and X₂₂-X₂₄ are absent, and wherein:

-   -   X₆ is a glycine residue or absent,     -   X₇ is a tyrosine residue or absent,     -   X₈ is a glutamine residue or absent,     -   X₉ is a lysine residue or absent,     -   X₁₀ is a lysine residue or absent,     -   X₁₁ is a leucine residue or absent,     -   X₁₂ is an arginine residue or absent,     -   X₁₃ is a serine residue or absent,     -   X₁₄ is a methionine residue or absent,     -   X₁₅ is a threonine residue,     -   X₁₆ is an aspartic acid residue,     -   X₁₇ is a lysine residue,     -   X₁₈ is a tyrosine residue,     -   X₁₉ is an arginine residue,     -   X₂₀ is a leucine residue, and     -   X₂₁ is a histidine residue.

In another specific aspect, X₁-X₅ and X₂₂-X₂₄ are absent, and wherein:

-   -   X₆ is a glycine residue,     -   X₇ is a tyrosine residue,     -   X₈ is a glutamine residue,     -   X₉ is a lysine residue,     -   X₁₀ is a lysine residue,     -   X₁₁ is a leucine residue,     -   X₁₂ is an arginine residue,     -   X₁₃ is a serine residue or absent,     -   X₁₄ is a methionine residue or absent,     -   X₁₅ is threonine residue or absent,     -   X₁₆ is an aspartic acid residue or absent,     -   X₁₇ is a lysine residue or absent,     -   X₁₈ is a tyrosine residue or absent,     -   X₁₉ is an arginine residue or absent,     -   X₂₀ is a leucine residue or absent, and     -   X₂₁ is a histidine residue or absent.

In another embodiment, compounds wherein X₁-X₅ and X₂₁-X₂₄ are absent, wherein at least seven contiguous amino acid residues are present, and wherein:

-   -   X₆ is a glycine residue or absent,     -   X₇ is a tyrosine residue or absent,     -   X₈ is a glutamine residue or absent,     -   X₉ is a lysine residue or absent,     -   X₁₀ is a lysine residue or absent,     -   X₁₁ is a leucine residue or absent,     -   X₁₂ is a an arginine residue or absent,     -   X₁₃ is a serine residue or absent,     -   X₁₄ is a methionine residue or absent     -   X₁₅ is a threonine residue or absent,     -   X₁₆ is an aspartic acid residue or absent,     -   X₁₇ is a lysine residue or absent,     -   X₁₈ is a tyrosine residue or absent,     -   X₁₉ is an arginine residue or absent, and     -   X₂₀ is a leucine residue or absent.

In a further embodiment,

-   -   X₃ is a leucine residue or absent,     -   X₄ is a glycine residue or absent,     -   X₅ is a serine residue, a d-serine residue or absent,     -   X₆ is a glycine residue, a histidine residue, a lysine residue         or absent,     -   X₇ is a tyrosine residue or an arginine residue,     -   X₈ is a glutamine residue, or a methionine residue,     -   X₉ is a lysine residue,     -   X₁₀ is a lysine residue or a threonine residue,     -   X₁₁ is a leucine residue or a serine residue,     -   X₁₂ is an arginine residue, or a leucine residue,     -   X₁₃ is a serine residue, or a tyrosine residue,     -   X₁₄ is a serine residue, a leucine residue, an isoleucine         residue, or an aspartic acid residue,     -   X₁₅ is a threonine residue or a glycine residue,     -   X₁₆ is an aspartic acid residue or an arginine residue,     -   X₁₇ is a methionine residue or absent,     -   X₁₈ is a glutamine residue or absent,     -   X₁₉ is, a tyrosine residue or absent,     -   X₂₀ is a leucine residue, a isoleucine residue, an arginine         residue, a valine residue or absent,     -   X₂₁ is a histidine residue, a lysine residue, or absent,     -   X₂₂ is a leucine residue or absent,     -   X₂₃ is a serine residue or absent, and     -   X₂₄ is a valine residue or absent.

In a more specific embodiment, the compounds are selected from any one of Compound Nos. 1-73 and 117-194 or a pharmaceutically acceptable salt thereof. For example, the compound is selected from any one of Compounds Nos. 1-73 or a pharmaceutically acceptable salt thereof. In another example the compound is selected from any one of Compound Nos. 117-194 or a pharmaceutically acceptable salt thereof.

In a more specific embodiment, the compound is selected from:

or a pharmaceutically acceptable salt thereof.

In a fourth aspect, P comprises at least 3 contiguous amino acids of the i2 loop.

In a specific embodiment of the fourth aspect, the i2 loop of the CXCR4 receptor from which P is derived has the following sequence:

(SEQ ID NO: 371) DRYLAIVHATNSQRPRKLLAEK.

In another embodiment of the fourth aspect, P is a sequence selected from SEQ ID NOS:149-199:

CXCR4 SEQ ID i-Loop Sequence NO: i2 DRYLAIVHATNSQRPRKLLAEK 149 i2 DRYLAIVHATNSQRPRKLLAE 150 i2 DRYLAIVHATNSQRPRKLLA 151 i2 DRYLAIVHATNSQRPRKLL 152 i2 DRYLAIVHATNSQRPRKL 153 i2 DRYLAIVHATNSQRPRK 154 i2 DRYLAIVHATNSQRPR 155 i2 DRYLAIVHATNSQRP 156 i2 DRYLAIVHATNSQR 157 i2 DRYLAIVHATNSQ 158 i2 DRYLAIVHATNS 159 i2 DRYLAIVHATN 160 i2 DRYLAIVHAT 161 i2 DRYLAIVHA 162 i2 DRYLAIVH 163 i2 DRYLAIV 164 i2 RYLAIVHATNSQRPRKLLAEK 165 i2 YLAIVHATNSQRPRKLLAEK 166 i2 LAIVHATNSQRPRKLLAEK 167 i2 AIVHATNSQRPRKLLAEK 168 i2 IVHATNSQRPRKLLAEK 169 i2 VHATNSQRPRKLLAEK 170 i2 HATNSQRPRKLLAEK- 171 i2 ATNSQRPRKLLAEK 172 i2 TNSQRPRKLLAEK 173 i2 NSQRPRKLLAEK 174 i2 SQRPRKLLAEK 175 i2 QRPRKLLAEK 176 i2 RPRKLLAEK 177 i2 PRKLLAEK 178 i2 RKLLAEK 179 i2 RYLAIVH- 180 i2 YLAIVHA 181 i2 LAIVHAT 182 i2 AIVHATN- 183 i2 IVHATNS- 184 i2 VHATNSQ 185 i2 HATNSQR 186 i2 ATNSQRP 187 i2 TNSQRPR- 188 i2 NSQRPRK 189 i2 SQRPRKL 190 i2 QRPRKLL 191 i2 RPRKLLA 192 i2 PRKLLAE 193 i2 VHATNSQRPRKLLAEKVVY 194 i2 VHATNSQRPRKLLA 195 i2 HATNSQRPRKL 196 i2 HATNSQRPRKLLA 197 i2 HATNSQRPRKLLAE 198 i2 HATNSQRPRKLLAEKV 199

In a more specific embodiment, a compound of the invention is represented by Formula B or a pharmaceutically acceptable salt thereof: wherein

T-L-Y₁-Y₂-Y₃-Y₄-Y₅-Y₆-Y₇-Y₈-Y₉-Y₁₀-Y₁₁-Y₁₂-Y₁₃-Y₁₄-Y₁₅-Y₁₆-Y₁₇-Y₁₈-Y₁₉-Y₂₀-Y₂₁-Y₂₂-Y₂₃-Y₂₄-Y₂₅-R₁,

wherein L is a linking moiety represented by C(O) and bonded to the N terminal nitrogen of Y₁ or the next present amino acid residue if Y₁ is absent; T is a lipophilic tether moiety bonded to L; and R₁ is OR₂ or N(R₂)₂, each R₂ is independently H or alkyl, wherein at least three contiguous Y₁-Y₂₅ amino acid residues are present and wherein at least one of Y₁-Y₂₂ is absent, a d-amino acid residue or an alanine residue, and wherein:

-   -   Y₁ is an aspartic acid residue, a d-aspartic acid residue, an         alanine residue or absent,     -   Y₂ is an arginine residue, a d-arginine residue, an alanine         residue or absent,     -   Y₃ is a tyrosine residue, a d-tyrosine residue, an alanine         residue or absent,     -   Y₄ is a leucine residue, a d-leucine residue, an alanine residue         or absent,     -   Y₅ is an alanine residue, a d-alanine residue or absent,     -   Y₆ is an isoleucine residue, a d-isoleucine residue, an alanine         residue or absent,     -   Y₇ is a valine residue, a d-valine acid residue, an alanine         residue or absent,     -   Y₈ is a histidine residue a d-histidine residue, an alanine         residue or absent,     -   Y₉ is an alanine residue, a d-alanine residue or absent,     -   Y₁₀ is a threonine residue, a d-threonine residue, an alanine         residue or absent,     -   Y₁₁ is an asparagine residue, a d-asparagine residue, an alanine         residue or absent,     -   Y₁₂ is a serine residue, a d-serine residue, an alanine residue         or absent,     -   Y₁₃ is a glutamine residue, a d-glutamine residue, an alanine         residue or absent,     -   Y₁₄ is an arginine residue, a d-arginine residue, an alanine         residue or absent,     -   Y₁₅ is a proline residue, a d-proline residue, an alanine         residue or absent,     -   Y₁₆ is an arginine residue, a d-arginine residue, an alanine         residue or absent,     -   Y₁₇ is a lysine residue, a d-lysine residue, an alanine residue         or absent,     -   Y₁₈ is a leucine residue, a d-leucine residue, an alanine         residue or absent,     -   Y₁₉ is a leucine residue, a d-leucine residue, an alanine         residue or absent,     -   Y₂₀ is an alanine residue, a d-alanine, an isoleucine residue, a         d-isoleucine residue, an arginine residue, a d-arginine residue,         a valine residue, a d-valine or absent,     -   Y₂₁ is a glutamic acid residue, a d-glutamic acid residue, an         alanine residue, a d-alanine residue or absent,     -   Y₂₂ is a lysine residue, a d-lysine residue, an alanine residue         or absent,     -   Y₂₃ is a valine residue, a d-valine residue or absent,     -   Y₂₄ is a valine residue, a d-valine residue or absent, and     -   Y₂₅ is a tyrosine residue, a d-tyrosine residue or absent.

In another embodiment of Formula B, the compound is represented by wherein Y₂₃-Y₂₅ are absent, and wherein:

-   -   Y₁ is an aspartic acid residue,     -   Y₂ is an arginine residue,     -   Y₃ is a tyrosine residue,     -   Y₄ is a leucine residue,     -   Y₅ is an alanine,     -   Y₆ is an isoleucine residue,     -   Y₇ is a valine residue,     -   Y₈ is a histidine residue,     -   Y₉ is an alanine or absent,     -   Y₁₀ is a threonine or absent,     -   Y₁₁ is an asparagine or absent,     -   Y₁₂ is a serine residue or absent,     -   Y₁₃ is a glutamine residue or absent,     -   Y₁₄ is an arginine residue or absent,     -   Y₁₅ is a proline residue or absent,     -   Y₁₆ is an arginine residue or absent,     -   Y₁₇ is a lysine residue or absent,     -   Y₁₈ is a leucine residue,     -   Y₁₉ is a leucine residue,     -   Y₂₀ is an alanine residue or absent,     -   Y₂₁ is a glutamic acid residue or absent, and     -   Y₂₂ is a lysine residue or absent.

In yet another aspect, the compound of Formula B comprises, when Y₁ and

-   -   Y₂₃-Y₂₅ are absent, and wherein:     -   Y₂ is an arginine residue or absent,     -   Y₃ is a tyrosine residue or absent,     -   Y₄ is a leucine residue or absent,     -   Y₅ is an alanine residue or absent,     -   Y₆ is an isoleucine residue or absent,     -   Y₇ is a valine residue or absent,     -   Y₈ is a histidine residue or absent,     -   Y₉ is an alanine or absent,     -   Y₁₀ is a threonine or absent,     -   Y₁₁ is an asparagine or absent,     -   Y₁₂ is a serine residue or absent,     -   Y₁₃ is a glutamine residue or absent,     -   Y₁₄ is an arginine residue or absent,     -   Y₁₅ is a proline residue or absent,     -   Y₁₆ is an arginine residue or absent,     -   Y₁₇ is a lysine residue,     -   Y₁₈ is a leucine residue,     -   Y₁₉ is a leucine residue,     -   Y₂₀ is an alanine residue,     -   Y₂₁ is a glutamic acid residue, and     -   Y₂₂ is a lysine residue.     -   In another specific embodiment of a compound represented by         Formula B, comprises when Y₂₃-Y₂₅ are absent and wherein seven         contiguous Y₁-Y₂₂ amino acid residues are present, and wherein,     -   Y₁ is an aspartic acid residue or absent,

Y₂ is an arginine residue or absent,

-   -   Y₃ is a tyrosine residue or absent,     -   Y₄ is a leucine residue or absent,     -   Y₅ is an alanine residue or absent,     -   Y₆ is an isoleucine residue or absent,     -   Y₇ is a valine residue or absent,     -   Y₈ is a histidine residue or absent,     -   Y₉ is an alanine residue or absent,     -   Y₁₀ is a threonine residue or absent,     -   Y₁₁ is an asparagine residue or absent,     -   Y₁₂ is a serine residue or absent,     -   Y₁₃ is a glutamine residue or absent,     -   Y₁₄ is an arginine residue or absent;     -   Y₁₅ is a proline residue or absent,     -   Y₁₆ is an arginine residue or absent,     -   Y₁₇ is a lysine residue or absent,     -   Y₁₈ is a isoleucine residue or absent,     -   Y₁₉ is a leucine residue or absent,     -   Y₂₀ is an alanine residue or absent,     -   Y₂₁ is a glutamic acid residue or absent, and     -   Y₂₂ is a lysine residue or absent.

In a more specific embodiment of a compound represented by Formula B,

-   -   when Y₁-Y₆ are absent and wherein:     -   Y₇ is a valine residue or absent,     -   Y₈ is a histidine residue,     -   Y₉ is a alanine residue,     -   Y₁₀ is a threonine residue,     -   Y₁₁ is an asparagine residue,     -   Y₁₂ is a serine residue,     -   Y₁₃ is a glutamine residue,     -   Y₁₄ is an arginine residue,     -   Y₁₅ is a proline residue,     -   Y₁₆ is an arginine residue,     -   Y₁₇ is a lysine residue,     -   Y₁₈ is a leucine residue,     -   Y₁₉ is a leucine residue or absent,     -   Y₂₀ is an alanine residue or absent,     -   Y₂₁ is a glutamic acid or absent,     -   Y₂₂ is a lysine residue or absent,     -   Y₂₃ is a valine lysine residue or absent,     -   Y₂₄ is a valine residue or absent, and     -   Y₂₅ is a tyrosine residue or absent.

In a more specific embodiment of Formula B, the CXCR4 compound is selected from any one of the Compound Nos. 74-83 or a pharmaceutically acceptable salt thereof.

In a fifth aspect, P comprises at least 3 contiguous amino acids of the i3 loop.

In a specific embodiment of the fifth aspect, the i3 loop of the CXCR4 receptor from which P is derived has the following sequence:

(SEQ ID NO: 372) IIISKLSHSKGHQKRKALKTTVI.

In another embodiment of the fifth aspect, P is a sequence selected from:

CXCR4 i-Loop Sequence SEQ ID: i3 HSKKGHQKRKALK 200 i3 JGYQKKLRSJTD 201 i3 IIISKLSHSKGHQKRKALKT 202 i3 IIISKLSHSKGHQKRKALK 203 i3 IIISKLSHSKGHQKRKAL 204 i3 IIISKLSHSKGHQKRKA 205 i3 IIISKLSHSKGHQKRK 206 i3 IIISKLSHSKGHQKR 207 i3 IIISKLSHSKGHQK 208 i3 IIISKLSHSKGHQ 209 i3 IIISKLSHSKGH 210 i3 IIISKLSHSKG 211 i3 IIISKLSHSK 212 i3 IIISKLSHS 213 i3 IIISKLSH 214 i3 IIISKLS 215 i3 IISKLSHSKGHQKRKALKT 216 i3 ISKLSHSKGHQKRKALKT 217 i3 SKLSHSKGHQKRKALKT 218 i3 KLSHSKGHQKRKALKT 219 i3 LSHSKGHQKRKALKT 220 i3 SHSKGHQKRKALKT 221 i3 HSKGHQKRKALKT 222 i3 SKGHQKRKALKT 223 i3 KGHQKRKALKT 224 i3 GHQKRKALKT 225 i3 HQKRKALKT 226 i3 QKRKALKT 227 i3 KRKALKT 228 i3 IISKLSH 229 i3 ISKLSHS 230 i3 SKLSHSK 231 i3 KLSHSKG 232 i3 LSHSKGH 233 i3 SHSKGHQ 234 i3 HSKGHQK 235 i3 SKGHQKR 236 i3 KGHQKRK 237 i3 GHQKRKA 238 i3 HQKRKAL 239 i3 QKRKALK 240 i3 HSKGHQKRKALKTT 241 i3 HSKGHQKRKALKTTV 242 i3 HSKGHQKRKALKTTVI 243 i3 HSKGHQKRKQALK 244 i3 KLSHSKGHQKRKA 245 i3 KLSHSKGHQKRKAL 246 i3 KLSHSKGHQKRKALK 247 i3 KLSHSKGHQKRKALKTTV 248 i3 KLSHSKGHQKRKALKTTVIL 249 i3 LSHSKGHQKRKALK 250 i3 SHSKGHQKRKALK 251 i3 SKLSHSKGHQKRKALK 252 i3 SKLSHSKGHQKRKALKTTVIL 253 i3 QHLHIALKKSTSRKVKSGTLK 254

In another aspect, a CXCR4 compound of the invention is represented by Formula C or a pharmaceutically acceptable salt thereof:

T-L-W₁-W₂-W₃-W₄-W₅-W₆-W₇-W₈-W₉-W₁₀-W₁₁-W₁₂-W₁₃-W₁₄-W₁₅-W₁₆-W₁₇-W₁₈-W₁₉-W₂₀-W₂₁-W₂₂-W₂₃-W₂₄-W₂₅-W₂₆-W₂₇-W₂₈-W₂₉-W₃₀-W₃₁-W₃₂-R₁;

wherein L is a linking moiety represented by C(O) and bonded to W₁ at an N terminal nitrogen of W₁ or the next present amino acid residue if W₁ is absent; T is a lipophilic tether moiety bonded to L; R₁ is OR₂ or N(R₂)₂, each R₂ is independently H or alkyl, wherein at least three contiguous W₁-W₃₂ are present, and wherein: W₁ is an isoleucine residue, a d-isoleucine residue, an alanine residue or absent, W₂ is isoleucine residue, a d-isoleucine residue, an alanine residue or absent, W₃ is isoleucine residue, a d-isoleucine residue, an alanine residue or absent, W₄ is a serine residue, a d-serine residue, an alanine residue or absent, W₅ is a lysine residue, a d-lysine residue, an alanine residue or absent, W₆ is a leucine residue, a histidine residue, a d-leucine residue, an alanine residue or absent, W₇ is a serine residue, a d-serine residue, an alanine residue or absent, W₈ is a histidine residue, a d-histidine residue, an alanine residue or absent, W₉ is a serine residue, a d-serine residue, an alanine residue a lysine residue, or absent, W₁₀ is a lysine residue, a d-lysine residue, an alanine residue, a leucine residue, an isoleucine residue or absent, W₁₁ is glycine residue, a d-glycine residue, an alanine residue or absent, W₁₂ is a histidine residue, a d-histidine residue, an alanine residue a tyrosine residue or absent, W₁₃ is a glutamine residue, a d-glutamine residue, an alanine residue or absent, W₁₄ is a lysine residue, a d-lysine residue, an alanine residue or absent; W₁₅ is an arginine residue, a d-arginine residue, an alanine residue, a lysine residue or absent, W₁₆ is a lysine residue, a d-lysine residue, an alanine residue, a leucine residue or absent, W₁₇ is an alanine, d-alanine, an arginine residue or absent, W₁₈ is a leucine residue, a d-leucine residue, an alanine residue, a serine residue or absent, W₁₉ is a lysine residue, a d-lysine residue, an alanine residue, a leucine residue, an isoleucine residue or absent, W₂₀ is threonine, a d-threonine residue, an alanine residue leucine residue or absent, W₂₁ is threonine, a d-threonine residue, an alanine residue a lysine residue or aspartic acid or absent, W₂₂ is a valine, a d-valine residue, an alanine residue or absent, W₂₃ is isoleucine residue, a d-isoleucine residue, an alanine residue a serine residue or absent, W₂₄ is leucine residue, a d-leucine residue, an alanine residue an arginine residue or absent, W₂₅ is a lysine residue, a d-lysine residue, an alanine residue or absent, W₂₆ is a valine residue, a d-valine residue, an alanine residue or absent, W₂₇ is a lysine residue, a d-lysine residue, an alanine residue or absent, W₂₈ is a serine residue a d-serine residue, an alanine residue or absent, W₂₉ is a glycine residue, a d-glycine residue, an alanine residue or absent, W₃₀ is a threonine residue, a d-threonine residue, an alanine residue or absent, W₃₁ is a leucine residue, a d-leucine residue, an alanine residue or absent, W₃₂ is a lysine residue, a d-lysine residue, an alanine residue or absent, wherein when W₂₀-W₃₂ is absent at least one of W₁-W₂₃ is also absent and wherein when W₁-W₇ and W₂₀-W₃₂ is absent, at least one of W₈-W₁₉ is absent, a d-amino acid or alanine.

In another aspect, a CXCR4 compound is represented by W₂₄-W₃₂ are absent and wherein:

-   -   W₁ is an isoleucine residue,     -   W₂ is an isoleucine residue,     -   W₃ is an isoleucine residue,     -   W₄ is a serine residue,     -   W₅ is a lysine residue,     -   W₆ is a leucine residue,     -   W₇ is a serine residue,     -   W₈ is a histidine residue or absent,     -   W₉ is a serine residue, or absent,     -   W₁₀ is a lysine residue or absent,     -   W₁₁ is a glycine residue or absent,     -   W₁₂ is a histidine residue, or absent,     -   W₁₃ is a glutamine residue or absent,     -   W₁₄ is a lysine residue or absent,     -   W₁₅ is an arginine residue or absent,     -   W₁₆ is a lysine residue or absent,     -   W₁₇ is an alanine residue or absent,     -   W₁₈ is a leucine residue or absent,     -   W₁₉ is a lysine residue or absent,     -   W₂₀ is a threonine residue or absent,     -   W₂₁ is a threonine residue or absent,     -   W₂₂ is a valine residue or absent, and     -   W₂₃ is an isoleucine residue or absent.

In another aspect, the CXCR 4 compounds of the invention are represented when W₁, W₂₁-W₃₂ are absent and wherein:

-   -   W₂ is an isoleucine residue or absent,     -   W₃ is an isoleucine residue or absent, W₄ is a serine residue or         absent,     -   W₅ is a lysine residue or absent,     -   W₆ is a leucine residue or absent,     -   W₇ is a serine residue or absent,     -   W₈ is a histidine residue or absent,     -   W₉ is a serine residue, or absent,     -   W₁₀ is a lysine residue or absent,     -   W₁₁ is a glycine residue or absent,     -   W₁₂ is a histidine residue, or absent,     -   W₁₃ is a glutamine residue or absent,     -   W₁₄ is a lysine residue,     -   W₁₅ is an arginine residue,     -   W₁₆ is a lysine residue,     -   W₁₇ is an alanine residue,     -   W₁₈ is a leucine residue,     -   W₁₉ is a lysine residue, and     -   W₂₀ is a threonine residue.

In yet another embodiment, the CXCR4 compounds of the invention comprise seven contiguous amino acid residues of W₁-W₁₉ are present and wherein:

-   -   W₁ is an isoleucine residue or absent,     -   W₂ is an isoleucine residue or absent,     -   W₃ is an isoleucine residue or absent,     -   W₄ is a serine residue or absent,     -   W₅ is a lysine residue or absent,     -   W₆ is a leucine residue or absent,     -   W₇ is a serine residue or absent,     -   W₈ is a histidine residue or absent,     -   W₉ is a serine residue, or absent,     -   W₁₀ is a lysine residue or absent,     -   W₁₁ is a glycine residue or absent,     -   W₁₂ is a histidine residue, or absent,     -   W₁₃ is a glutamine residue or absent,     -   W₁₄ is a lysine residue or absent,     -   W₁₅ is an arginine residue or absent,     -   W₁₆ is a lysine residue or absent,     -   W₁₇ is an alanine residue or absent,     -   W₁₈₁ is a leucine residue or absent, and     -   W₁₉ is a lysine residue or absent,

In yet another embodiment, the CXCR4 compounds are represented when W₁. W₃ are absent and W₂₅-W₃₂ are absent, and wherein:

-   -   W₄ is a serine residue or absent,     -   W_(s) is a lysine residue or absent,     -   W₆ is a leucine residue or absent,     -   W₇ is a serine residue or absent,     -   W₈ is a histidine residue,     -   W₉ is a serine residue,     -   W₁₀ is a lysine residue,     -   W₁₁ is a glycine residue,     -   W₁₂ is a histidine residue,     -   W₁₃ is a glutamine residue,     -   W₁₄ is a lysine residue,     -   W₁₅ is an arginine residue,     -   W₁₆ is a lysine residue,     -   W₁₇ is alanine or a glutamine residue,     -   W₁₈ is leucine residue alanine or absent,     -   W₁₉ is a lysine residue, leucine residue or absent,     -   W₂₀ is threonine or absent,     -   W₂₁ is threonine or absent,     -   W₂₂ is a valine residue or absent,     -   W₂₃ is isoleucine residue or absent,     -   W₂₄ is leucine residue or absent.

In a more specific embodiment of Formula C, the compound is selected from any one of the Compound Nos. 84, 87-106 or a pharmaceutically acceptable salt thereof.

In yet another embodiment, a CXCR4 compound of the invention is selected from one of the following compounds or a pharmaceutically acceptable salt thereof:

or a pharmaceutically acceptable salt thereof.

In a sixth aspect, P comprises at least 3 contiguous amino acids of the i4 domain.

In a specific embodiment of the sixth aspect, the i4 domain of the CXCR4 receptor from which P is derived has the following sequence:

(SEQ ID NO: 373) GAKFKTSAQHALTSVSRGSSLKILSKGKRGGHSSVSTESESSSFHSS.

In another embodiment of the sixth aspect, P is a sequence selected from:

CXCR4 SEQ ID i-Loop Sequence NO: i4 GAKFKTSAQHALTSVSRGSSLKILSKGKRGGHSSVSTESESSSFH 255 i4 GAKFKTSAQHALTSVSRGSSLKILSKGKRGGHSSVSTESESSSF 256 i4 GAKFKTSAQHALTSVSRGSSLKILSKGKRGGHSSVSTESESSS 257 i4 GAKFKTSAQHALTSVSRGSSLKILSKGKRGGHSSVSTESESS 258 i4 GAKFKTSAQHALTSVSRGSSLKILSKGKRGGHSSVSTESES 259 i4 GAKFKTSAQHALTSVSRGSSLKILSKGKRGGHSSVSTESE 260 i4 GAKFKTSAQHALTSVSRGSSLKILSKGKRGGHSSVSTES 261 i4 GAKFKTSAQHALTSVSRGSSLKILSKGKRGGHSSVSTE 262 i4 GAKFKTSAQHALTSVSRGSSLKILSKGKRGGHSSVST 263 i4 GAKFKTSAQHALTSVSRGSSLKILSKGKRGGHSSVS 264 i4 GAKFKTSAQHALTSVSRGSSLKILSKGKRGGHSSV 265 i4 GAKFKTSAQHALTSVSRGSSLK1LSKGKRGGHSS 266 i4 GAKFKTSAQHALTSVSRGSSLKILSKGKRGGHS 267 i4 GAKFKTSAQHALTSVSRGSSLKILSKGKRGGH 268 i4 GAKFKTSAQHALTSVSRGSSLKILSKGKRGG 269 i4 GAKFKTSAQHALTSVSRGSSLKILSKGKRG 270 i4 GAKFKTSAQHALTSVSRGSSLKILSKGKR 271 i4 GAKFKTSAQHALTSVSRGSSLKILSKGK 272 i4 GAKFKTSAQHALTSVSRGSSLKILSKG 273 i4 GAKFKTSAQHALTSVSRGSSLKILSK 274 i4 GAKFKTSAQHALTSVSRGSSLKILS 275 i4 GAKFKTSAQHALTSVSRGSSLKIL 276 i4 GAKFKTSAQHALTSVSRGSSLKI 277 i4 GAKFKTSAQHALTSVSRGSSLK 278 i4 GAKFKTSAQHALTSVSRGSSL 279 i4 GAKFKTSAQHALTSVSRGSS 280 i4 GAKFKTSAQHALTSVSRGS 281 i4 GAKFKTSAQHALTSVSRG 282 i4 GAKFKTSAQHALTSVSR 283 i4 GAKFKTSAQHALTSVS 284 i4 GAKFKTSAQHALTSV 285 i4 GAKFKTSAQHALTS 286 i4 GAKFKTSAQHALT 287 i4 GAKFKTSAQHAL 288 i4 GAKFKTSAQHA 289 i4 GAKFKTSAQH 290 i4 AKFKTSAQHALTSVSRGSSLKILSKGKRGGHSSVSTESESSSFHSS 291 i4 KFKTSAQHALTSVSRGSSLKILSKGKRGGHSSVSTESESSSFHSS 292 i4 FKTSAQHALTSVSRGSSLKILSKGKRGGHSSVSTESESSSFHSS 293 i4 KTSAQHALTSVSRGSSLKILSKGKRGGHSSVSTESESSSFHSS 294 i4 TSAQHALTSVSRGSSLKILSKGKRGGHSSVSTESESSSFHSS 295 i4 SAQHALTSVSRGSSLKILSKGKRGGHSSVSTESESSSFHSS 296 i4 AQHALTSVSRGSSLKILSKGKRGGHSSVSTESESSSFHSS 297 i4 QHALTSVSRGSSLKILSKGKRGGHSSVSTESESSSFHSS 298 i4 HALTSVSRGSSLKILSKGKRGGHSSVSTESESSSFHSS 299 i4 ALTSVSRGSSLKILSKGKRGGHSSVSTESESSSFHSS 300 i4 LTSVSRGSSLKILSKGKRGGHSSVSTESESSSFHSS 301 i4 TSVSRGSSLKILSKGKRGGHSSVSTESESSSFHSS 302 i4 SVSRGSSLKILSKGKRGGHSSVSTESESSSFHSS 303 i4 VSRGSSLKILSKGKRGGHSSVSTESESSSFHSS 304 i4 SRGSSLKILSKGKRGGHSSVSTESESSSFHSS 305 i4 RGSSLKILSKGKRGGHSSVSTESESSSFHSS 306 i4 GSSLKILSKGKRGGHSSVSTESESSSFHSS 307 i4 SSLKILSKGKRGGHSSVSTESESSSFHSS 308 i4 SLKILSKGKRGGHSSVSTESESSSFHSS 309 i4 LKILSKGKRGGHSSVSTESESSSFHSS 310 i4 KILSKGKRGGHSSVSTESESSSFHSS 311 i4 ILSKGKRGGHSSVSTESESSSFHSS 312 i4 LSKGKRGGHSSVSTESESSSFHSS 313 i4 SKGKRGGHSSVSTESESSSFHSS 314 i4 KGKRGGHSSVSTESESSSFHSS 315 i4 GKRGGHSSVSTESESSSFHSS 316 i4 KRGGHSSVSTESESSSFHSS 317 i4 RGGHSSVSTESESSSFHSS 318 i4 GGHSSVSTESESSSFHSS 320 i4 GHSSVSTESESSSFHSS 321 i4 HSSVSTESESSSFHSS 322 i4 SSVSTESESSSFHSS 323 i4 SVSTESESSSFHSS 324 i4 VSTESESSSFHSS 325 i4 STESESSSFHSS 326 i4 TESESSSFHSS 327 i4 ESESSSFHSS 328 i4 AKFKTSAQHA 329 i4 KFKTSAQHAL 330 i4 FKTSAQHALT 331 i4 KTSAQHALTS 332 i4 TSAQHALTSV 333 i4 SAQHALTSVS 334 i4 AQHALTSVSR 335 i4 QHALTSVSRG 336 i4 HALTSVSRGS 337 i4 ALTSVSRGSS 338 i4 LTSVSRGSSL 339 i4 TSVSRGSSLK 340 i4 SVSRGSSLKI 341 i4 VSRGSSLKIL 342 i4 SRGSSLKILS 343 i4 RGSSLKILSK 345 i4 GSSLKILSKG 346 i4 SSLKILSKGK 347 i4 SLKILSKGKR 348 i4 LKILSKGKRG 349 i4 KILSKGKRGG 350 i4 ILSKGKRGGH 351 i4 LSKGKRGGHS 352 i4 SKGKRGGHSS 353 i4 KGKRGGHSSV 354 i4 GKRGGHSSVS 355 i4 KRGGHSSVST 356 i4 RGGHSSVSTE 357 i4 GGHSSVSTES 358 i4 GHSSVSTESE 359 i4 HSSVSTESES 360 i4 SSVSTESESS 361 i4 SVSTESESSS 362 i4 VSTESESSSF 363 i4 STESESSSFH 364 i4 TESESSSFHS 365 i4 ESESSSFHSS 366 i4 GAKFKTSAQHALTSVSRGSSLKILSKGKRGGHSSVSTESESSSFHS 367 i4 GAKFKTSAQHALTSVSRGSSLKILSKGKRGGHSCFH 368

In a another embodiment, CXCR4 compounds of the invention are represented by Formula D or a pharmaceutically acceptable salt thereof, wherein:

T-L-Z₁-Z₂-Z₃-Z₄-Z₅-Z₆-Z₇-Z₈-Z₉-Z₁₀-Z₁₁-Z₁₂-Z₁₃-Z₁₄-Z₁₅-Z₁₆-Z₁₇-Z₁₈-Z₁₉-Z₂₀-Z₂₁-Z₂₂-Z₂₃-Z₂₄-Z₂₅-Z₂₆-Z₂₇-Z₂₈-Z₂₉-Z₃₀-Z₃₁-Z₃₂-Z₃₃-Z₃₄-Z₃₅-Z₃₆-Z₃₇-Z₃₈-Z₃₉-Z₄₀-Z₄₁-Z₄₂-Z₄₃-Z₄₄-Z₄₅-Z₄₆-Z₄₇-R₁; wherein:

L is a linking moiety represented by C(O) and bonded to the N terminal nitrogen of Z₁ or the next present amino acid residue if Z₁ is absent;

and T is a lipophilic tether moiety bonded to L; R₁ is OR₂ or N(R₂)₂, each R₂ is independently H or alkyl, wherein at least three contiguous Z₁-Z₃₂ amino acid residues are present, and wherein:

-   -   Z₁ is a glycine residue, a d-glycine residue, an alanine residue         or absent,     -   Z₂ is an alanine residue a d-alanine residue or absent,     -   Z₃ is a lysine residue, a d-lysine residue, an alanine residue         or absent,     -   Z₄ is a phenylalanine residue, a d-phenylalanine residue, an         alanine residue or absent,     -   Z₅ is a lysine residue, a d-lysine residue, an alanine residue         or absent,     -   Z₆ is a threonine residue, a d-threonine residue, an alanine         residue or absent,     -   Z₇ is a serine residue a d-serine residue, an alanine residue or         absent,     -   Z₈ is an alanine residue, a d-alanine residue or absent,     -   Z₉ is a glutamine residue, a d-glutamine residue, an alanine         residue or absent,     -   Z₁₀ is a histidine residue, a d-histidine residue, an alanine         residue or absent,     -   Z₁₁ is an alanine residue, a d-alanine residue or absent,     -   Z₁₂ is a leucine residue, a d-leucine residue, an alanine         residue or absent,     -   Z₁₃ is a threonine residue, a d-threonine residue, an alanine         residue or absent,     -   Z₁₄ is a serine residue, a d-serine residue, an alanine residue         or absent;     -   Z₁₅ is a valine residue, a d-valine residue, an alanine residue         or absent,     -   Z₁₆ is a serine residue, a d-serine residue, an alanine residue         or absent,     -   Z₁₇ is an arginine residue, a d-arginine residue, an alanine         residue or absent,

Z₁₈ is a glycine residue, a d-glycine residue, an alanine residue or absent,

Z₁₉ is a serine residue, a d-serine residue, an alanine residue or absent,

-   -   Z₂₀ is a serine residue, a d-serine residue, an alanine residue         absent,     -   Z₂₁ is a leucine residue, a d-leucine residue, an alanine         residue or absent,     -   Z₂₂ is a lysine residue, a d-lysine residue, an alanine residue         or absent,     -   Z₂₃ is a isoleucine residue, a d-isoleucine residue, an alanine         residue a serine residue or absent,     -   Z₂₄ is a leucine residue, a d-leucine residue, an alanine         residue or absent,     -   Z₂₅ is a serine residue, a d-serine residue, an alanine residue         or absent,     -   Z₂₆ is a lysine residue, a d-lysine residue, an alanine residue         or absent,     -   Z₂₇ is glycine residue, a d-glycine residue, an alanine residue         or absent,     -   Z₂₈ is a lysine residue, a d-lysine residue, an alanine residue         or absent,     -   Z₂₉ is an arginine residue, a d-arginine residue, an alanine         residue or absent,     -   Z₃₀ is a glycine residue, a d-glycine residue, an alanine         residue or absent,     -   Z₃₁ is a glycine residue, a d-glycine residue, an alanine         residue or absent,     -   Z₃₂ is a histidine residue, a d-histidine residue, an alanine         residue or absent,     -   Z₃₃ is a serine residue, a d-serine residue, an alanine residue         or absent,     -   Z₃₄ is a serine residue, a d-serine residue, an alanine residue         cysteine, or absent,     -   Z₃₅ is a valine residue, a d-valine residue, an alanine residue         a phenylalanine residue, or absent,     -   Z₃₆ is a serine residue, a d-serine residue, an alanine residue         a histidine residue or absent,     -   Z₃₇ is a threonine residue, a d-threonine residue, an alanine         residue or absent,     -   Z₃₈ is a glutamic acid residue, a d-glutamic acid residue, an         alanine residue or absent,     -   Z₃₉ is a serine residue, a d-serine residue, an alanine residue         or absent,     -   Z₄₀ is a glutamic acid, a d-glutaminc acid residue, an alanine         residue or absent     -   Z₄₁ is a serine residue, a d-serine residue, an alanine residue         or absent,     -   Z₄₂ is a serine residue, a d-serine residue, an alanine residue         or absent,     -   Z₄₃ is a serine residue, a d-serine residue, an alanine residue         or absent, Z₄₄ is a phenylalanine residue, a d-phenylalanine         residue, an alanine residue or absent,     -   Z₄₅ is a histidine residue, a d-histidine residue, an alanine         residue or absent,     -   Z₄₆ is a serine residue, a d-serine residue, an alanine residue         or absent,     -   Z₄₇ is a serine residue, a d-serine residue, an alanine residue         or absent,     -   wherein at least one of Z₁-Z₄₇ is absent.

In a more specific embodiment, the CXCR4 compounds of the invention are represented by the following:

-   -   Z₁ is a glycine residue,     -   Z₂ is an alanine residue,     -   Z₃ is a lysine residue,     -   Z₄ is a phenylalanine residue,     -   Z₅ is a lysine residue,     -   Z₆ is a threonine residue,     -   Z₇ is a serine residue,     -   Z₈ is an alanine residue,     -   Z₉ is a glutamine residue,     -   Z₁₀ is a histidine residue or absent,     -   Z₁₁ is an alanine residue or absent,     -   Z₁₂ is a leucine residue or absent,     -   Z₁₃ is a threonine residue or absent,     -   Z₁₄ is a serine residue or absent,     -   Z₁₅ is a valine residue or absent,     -   Z₁₆ is a serine residue or absent,     -   Z₁₇ is an arginine residue or absent,     -   Z₁₈ is a glycine residue or absent,     -   Z₁₉ is a serine residue or absent,     -   Z₂₀ is a serine residue or absent,     -   Z₂₁ is a leucine residue or absent,     -   Z₂₂ is a lysine residue or absent,     -   Z₂₃ is an isoleucine residue, a serine residue or absent,     -   Z₂₄ is a leucine residue or absent,     -   Z₂₅ is a serine residue or absent,     -   Z₂₆ is a lysine residue or absent,     -   Z₂₇ is a glycine residue or absent,     -   Z₂₈ is a lysine residue or absent,     -   Z₂₉ is an arginine residue or absent, Z₃₀ is a glycine residue         or absent,     -   Z₃₁ is a glycine residue or absent,     -   Z₃₂ is a histidine residue or absent,     -   Z₃₃ is a serine residue or absent,     -   Z₃₄ is a serine residue or absent,     -   Z₃₅ is a valine residue or absent,     -   Z₃₆ is a serine residue or absent,     -   Z₃₇ is a threonine residue or absent,     -   Z₃₈ is a glutamic acid residue or absent,     -   Z₃₉ is a serine residue or absent,     -   Z₄₀ is a glutamic acid residue or absent,     -   Z₄₁ is a serine residue or absent,

-   Z₄₂ is a serine residue or absent,     -   Z₄₃ is a serine residue or absent,     -   Z₄₄ is a phenylalanine residue or absent,     -   Z₄₅ is a histidine residue or absent,     -   Z₄₆ is a serine residue or absent, and     -   Z₄₇ is a serine residue or absent.

In yet another embodiment, the CXCR4 compounds of the invention are represented by:

-   -   Z₁ is a glycine residue or absent,     -   Z₂ is an alanine residue or absent,     -   Z₃ is a lysine residue or absent,     -   Z₄ is a phenylalanine residue or absent,     -   Z₅ is a lysine residue or absent,     -   Z₆ is a threonine residue or absent,     -   Z₇ is a serine residue or absent,     -   Z₈ is an alanine residue or absent,     -   Z₉ is a glutamine residue or absent,     -   Z₁₀ is a histidine residue or absent,     -   Z₁₁, is an alanine residue or absent,     -   Z₁₂ is a leucine residue or absent,     -   Z₁₃ is a threonine residue or absent,     -   Z₁₄ is a serine residue or absent,     -   Z₁₅ is a valine residue or absent,     -   Z₁₆ is a serine residue or absent,     -   Z₁₇ is an arginine residue or absent,     -   Z₁₈ is a glycine residue or absent,     -   Z₁₉ is a serine residue or absent,     -   Z₂₀ is a serine residue absent,     -   Z₂₁ is a leucine residue or absent,     -   Z₂₂ is a lysine residue or absent,     -   Z₂₃ is an isoleucine residue, or absent,     -   Z₂₄ is a leucine residue or absent,     -   Z₂₅ is a serine residue or absent,     -   Z₂₆ is a lysine residue or absent,     -   Z₂₇ is a glycine residue or absent,     -   Z₂₈ is a lysine residue or absent,     -   Z₂₉ is an arginine residue or absent,     -   Z₃₀ is a glycine residue or absent,     -   Z₃₁ is a glycine residue or absent,     -   Z₃₂ is a histidine residue or absent,     -   Z₃₃ is a serine residue or absent,     -   Z₃₄ is a serine residue or absent,     -   Z₃₅ is a valine residue or absent,     -   Z₃₆ is a serine residue or absent,     -   Z₃₇ is a threonine residue or absent,     -   Z₃₈ is a glutamic acid residue,     -   Z₃₉ is a serine residue,     -   Z₄₀ is a glutamic acid residue,     -   Z₄₁ is a serine residue,     -   Z₄₂ is a serine residue,     -   Z₄₃ is a serine residue,     -   Z₄₄ is a phenylalanine residue,     -   Z₄₅ is a histidine residue,     -   Z₄₆ is a serine residue, and     -   Z₄₇ is a serine residue.

In a more specific embodiment, CXCR4 compounds of the invention are represented when Z₁ is absent, and 10 consecutive Z₂-Z₄₇ are present wherein:

-   -   Z₂ is an alanine residue or absent,     -   Z₃ is a lysine residue or absent,     -   Z₄ is a phenylalanine residue or absent,     -   Z₅ is a lysine residue or absent,     -   Z₆ is a threonine residue or absent,     -   Z₇ is a serine residue or absent,     -   Z₈ is an alanine residue or absent,     -   Z₉ is a glutamine residue or absent,     -   Z₁₀ is a histidine residue or absent,     -   Z₁₁ is an alanine residue or absent,     -   Z₁₂ is a leucine residue or absent,     -   Z₁₃ is a threonine residue or absent,     -   Z₁₄ is a serine residue or absent;     -   Z₁₅ is a valine residue or absent,     -   Z₁₆ is a serine residue or absent,     -   Z₁₇ is an arginine residue or absent,     -   Z₁₈ is a glycine residue or absent,     -   Z₁₉ is a serine residue or absent,     -   Z₂₀ is a serine residue absent,     -   Z₂₁ is leucine residue or absent,     -   Z₂₂ is a lysine residue or absent,     -   Z₂₃ is an isoleucine residue, or absent,     -   Z₂₄ is a leucine residue or absent,     -   Z₂₅ is a serine residue or absent,     -   Z₂₆ is a lysine residue or absent,     -   Z₂₇ is a glycine or absent,     -   Z₂₈ is a lysine residue or absent,     -   Z₂₉ is an arginine residue or absent,     -   Z₃₀ is a glycine residue or absent,     -   Z₃₁ is a glycine residue or absent,     -   Z₃₂ is a histidine residue or absent,     -   Z₃₃ is a serine residue or absent,     -   Z₃₄ is a serine residue or absent,     -   Z₃₅ is a valine residue or absent,     -   Z₃₆ is a serine residue or absent,     -   Z₃₇ is a threonine residue or absent,     -   Z₃₈ is a glutamic acid residue,     -   Z₃₉ is a serine residue,     -   Z₄₀ is glutamic acid residue,     -   Z₄₁ is a serine residue,     -   Z₄₂ is a serine residue,     -   Z₄₃ is a serine residue,     -   Z₄₄ is a phenylalanine residue,     -   Z₄₅ is a histidine residue,     -   Z₄₆ is a serine residue, and     -   Z₄₇ is a serine residue.

In a more specific embodiment of Formula D, the CXCR4 compound is selected from any one of the Compound Nos. 107-116 or a pharmaceutically acceptable salt thereof.

In a seventh aspect, T is an optionally substituted (C₆-C₃₀)alkyl, (C₆-C₃₀)alkenyl, (C₆-C₃₀)alkynyl, wherein 0-3 carbon atoms are replaced with oxygen, sulfur, nitrogen or a combination thereof. This value of T is applicable to the first, second, third, fourth, fifth and sixth aspects and the specific (i.e., specific, more specific and most specific) embodiments of same.

In a specific embodiment of the seventh aspect, T is selected from: CH₃(CH₂)₁₆, CH₃(CH₂)₁₅, CH₃(CH₂)₁₄, CH₃(CH₂)₁₃,CH₃(CH₂)₁₂, CH₃(CH₂)₁₁, CH₃(CH₂)₁₀, CH₃(CH₂)₉, CH₃(CH₂)₈, CH₃(CH₂)₉OPh-, CH₃(CH₂)₆C═C(CH₂)₆, CH₃(CH₂)₁₁O(CH₂)₃, and CH₃(CH₂)₉O(CH₂)₂.

In another specific embodiment of the seventh aspect, T is a fatty acid derivative.

In a more specific embodiment of the seventh aspect, the fatty acid is selected from the group consisting of: butyric acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, myristoleic acid, palmitoleic acid, oleic acid, linoleic acid, α-linolenic acid, arachidonic acid, eicosapentaenoic acid, erucic acid, docosahexaenoic acid.

In an eighth aspect, T is a bile acid derivative. This value of T is applicable to the first, second, third, fourth, fifth and sixth aspects and the specific (i.e., specific, more specific and most specific) embodiments of same.

In a specific embodiment of the eighth aspect, the bile acid is selected from the group consisting of: lithocholic acid, chenodeoxycholic acid, deoxycholic acid, cholanic acid, cholic acid, ursocholic acid, ursodeoxycholic acid, isoursodeoxycholic acid, lagodeoxycholic acid, dehydrocholic acid, hyocholic acid, and hyodeoxycholic acid.

In a ninth aspect, T is selected from sterols; progestagens; glucocorticoids; mineralcorticoids; androgens; and estrogens. This value of T is applicable to the first, second, third, fourth, fifth and sixth aspects and the specific (i.e., specific, more specific and most specific) embodiments of same.

In a tenth aspect, T-L of Formula I is represented by a moiety selected from the group consisting of:

CH₃(CH₂)₁₅—C(O);

CH₃(CH₂)₁₃—C(O);

CH₃(CH₂)₉O(CH₂)₂C(O);

CH₃(CH₂)₁₀O(CH₂)₂C(O);

CH₃(CH₂)₆C═C(CH₂)₆—C(O);

LCA-C(O); and

CH₃(CH₂)₉OPh-C(O) wherein

In an eleventh aspect, T of Formula I is represented by a moiety selected from the group consisting of:

In a twelfth aspect, the CXCR4 receptor compounds are selected from the compounds represented in Tables 6-13, excluding controls and those compounds not with the structure of Formula I or a pharmaceutically acceptable salt thereof.

TABLE 6  CXCR4 i1 loop compounds No.: Loop Sequence Lipid Comments MW 1 i1 AGYQKKLRSMT Pal 1635.024 D (SEQ ID NO. 11) 2 i1 MAYQKKLRSMT Pal 1709.168 D (SEQ ID NO. 12) 3 i1 MGAQKKLRSMT Pal 1603.046 D (SEQ ID NO. 13)  4 i1 MGYAKKLRSMT Pal 1638.09 D (SEQ ID NO. 14) 5 i1 MGYQKKLRAMT Pal 1679.142   D (SEQ ID NO. 15) 6 i1 MGYQKKLRSAT Pal 1635.024 D (SEQ ID NO. 16) 7 i1 MGYQKKLRSMA Pal 1665.116 D (SEQ ID NO. 17) 8 i1 MGYQKKLRSMT Pal 1651.132 A(SEQ ID NO. 18)  9 i1 MGYQAKLRSMT Pal 1638.047   D (SEQ ID NO. 19) 10 i1 MGYQKKLASMT Pal 1610.034 D (SEQ ID NO. 20)  11 i1 MGYQKALRSMT Pal 1638.047 D (SEQ ID NO. 21)  12 i1 MGYQKKARSMT Pal 1653.062 D (SEQ ID NO. 22)  13 i1 mGYQKKLRSMT Pal D- 1695.142 D (SEQ ID NO. 23) Methionine 14 i1 MGyQKKLRSMT Pal D-Tyrosine 1695.142 D (SEQ ID NO. 24)  15 i1 MGYqKKLRSMT Pal D- 1695.142 D (SEQ ID NO. 25) Glutamine 16 i1 MGYQkKLRS MT Pal D-Lysine 1695.142 D (SEQ ID NO. 26)  17 i1 MGYQKKLRSMT Pal D-Lysine 1695.142 D (SEQ ID NO. 27)  18 i1 MGYQKKIRSMT Pal D-Leucine 1695.142 D (SEQ ID NO. 28)  19 i1 MGYQKKLrSMT Pal D-Arginine 1695.142 D (SEQ ID NO. 29)  20 i1 MGYQKKLRsMT Pal D-Serine 1695.142 D (SEQ ID NO. 30) 21 i1 MGYQKKLRSmT Pal D- 1695.142 D (SEQ ID NO. 31) Methionine 22 i1 MGYQKKLRSMt Pal D- 1695.142 D (SEQ ID NO. 32) Threonine 23 i1 MGYQKKLRSMT Pal D-Aspartic 1695.142 d (SEQ ID NO. 33) acid 24 i1 GSHYQKKLRSST Pal 1744.043 D (SEQ ID NO. 34) 25 i1 SGYQKKLRSSTD Elaidic 1632.942 (SEQ ID NO. 1) 26 i1 SGYQKKLRSSTD Oleic 1618.915 (SEQ ID NO. 1) 27 i1 sGYQKKLRS STD Pal D-Serine 1606.904 (SEQ ID NO. 64) 28 i1 GSGYQKKLRSST Pal 1663.955 D (SEQ ID NO. 35) 29 i1 YQKKLRSSTD Pal 1462.776 (SEQ ID NO. 36) 30 i3 JGYQKKLRSJTD Pal 1659.065 (SEQ ID NO. 4) 31 i3 JGYQKKLRSJTD Pal 1645.038 (SEQ ID NO. 4) 32 MGYQKKLRSMT None capped 1498.77 (control) i1 D (SEQ ID NO. 376) peptide 33 i1 MGYQKKLRSMT C16H33 Pentadecyla- 1964.505 D (SEQ ID NO. 4) backbone lanine with Biotin 34 i1 LVMGYQKKLRS Pal 1907.43 MTD (SEQ ID NO. 78) 35 i1 VMGYQKKLRSM Pal 1794.273 TD (SEQ ID NO. 86) 36 i1 MGYQKKLRSMT Pal 1823.314 DK (SEQ ID NO. 79) 37 i1 MGYQKKLRSMT Pal 1986.487 DKY (SEQ ID NO. 80) 38 i1 MGYQKKLRSMT Pal 2255.831 DKYRL (SEQ ID NO. 82) 39 i1 MGYQKKLRSMT Pal 2506.127 DKYRLHL (SEQ ID NO. 83) 40 i1 YQKKLRSMTDK Pal 2504.088 YRLHLSV (SEQ ID NO. 77) 41 i1 KKLRSMTDKYR Pal 2212.786 LHLSV (SEQ ID NO. 74) 42 i1 KKLRSMTDKYR Pal 2026.578 LHL (SEQ ID NO. 73) 43 i1 KKLRSMTDKYR Pal 1913.42 LH (SEQ ID NO.) 44 i1 KKLRSMTDKYR Pal 1776.281 L (SEQ ID NO.) 45 i1 KKLRSMTDKYR Pal 1663.123 (SEQ ID NO.) 46 i1 KKLRSMTDKY Pal 1506.937 (SEQ ID NO.) 47 i1 MGYQKKLRSMT lipid on 2480.256 DKYRI (SEQ ID NO.) Pal both termini 48 i1 MGYQKKLRSMT Myr also on 2509.254 DKYRI (SEQ ID NO.) backbone 49 i1 MGYQKKLRSMT Pal 2255.831 DKYRI (SEQ ID NO.) 50 i1 SGYQKKLRSSTD Myr also 1860.328 (SEQ ID NO.) backbone lipid 51 i1 MGYQKKLRSMT Myr backbone 1948.565 D (SEQ ID NO.) NH(CH2)15- lipid also 52 i1 QKKLRSMTDKY CH3 1932.463 RI (SEQ ID NO.) 53 i1 MGYQKKLRSMT Pal C-terminus 2730.553 DKYRLHL (SEQ ID NO.) also 54 i1 MGYQKKLRSMT Myr dual lipid 2759.551 DKYRLHL (SEQ ID NO.) backbone 55 i1 MGYQKKLRSMT Pal 2692.336 DKYRLHLSV (SEQ ID NO.) 56 i1 MGYQKKLRSMT Myr dual lipid 2945.759 DKYRLHLSV backbone (SEQ ID NO.) 58 i1 MGYQKKLRSMT capped 1626.942 DK (SEQ ID NO.) peptide 59 i1 MGYQKKLRSMT NH(CH₂) 1851.367 DK (SEQ ID NO.) 15-CH3 60 i1 MGYQKKLRSMT Myr Dual 2076.737 DK (SEQ ID NO.) peptide Myr and C16 backbone 61 i1 KKLCRSMTDKC Pal 4, 11 Cys 1980.551 YRL (SEQ ID NO.) cyclization 62 i1 KKLRCSMTDCK Pal 5, 10 Cys 1980.551 YRL (SEQ ID NO.) cyclization 63 i1 KKLRSMTDKYR Pal head to tail 1802.318 L (SEQ ID NO.) cyclized 64 i1 KKLRSMTDKYR Pal 1820.333 L (SEQ ID NO.) 65 i1 KRMKTSLYDGR Pal scrambled 2255.831 MQYLK (SEQ ID NO.) No.: 39 66 i1 YTKRLDSHRKLK Pal scrambled 1913.42 M (SEQ ID NO.) No. 44 67 i1 MGYQKKLRSMT 2060:447 DKYRL (SEQ ID NO.) 68 i1 KKLRSXTDKYRL Pal X = Norluecine 1895.382 H (SEQ ID NO.) substitution 69 i1 SGYQKKLRSSTD Pal 1606.904 (SEQ ID NO. 1) 70 i1 SGYQKKLRSSTD Myr 1565.852 (SEQ ID NO. 1) 71 i1 SGYQKKLRSSTD Lca 1727.053 (SEQ ID NO. 1) 72 i1 MGYQKKLRSST Pal 1651.023 D (SEQ ID NO.) 73 i1 SGYQKKLRSMT Pal 1651.023 D (SEQ ID NO.) 117 i1 kKLRSMTDKYRL Pal H (SEQ ID NO. 89) 118 i1 KkLRSMTDKYRL Pal H (SEQ ID NO. 90) 119 i1 KKlRSMTDKYRL Pal H (SEQ ID NO. 91) 120 i1 KKLTSMTDKYRL Pal H (SEQ ID NO. 92) 121 i1 KKLRsMTDKYRL Pal H (SEQ ID NO. 93) 122 i1 KKLRSmTDKYR Pal LH (SEQ ID NO. 94) 123 i1 AKLRSMTDKYR Pal LH (SEQ ID NO. 95) 124 i1 KALRSMTDKYR Pal LH (SEQ ID NO. 96) 125 i1 KKARSMTDKYR Pal LH (SEQ ID NO. 97) 126 i1 KKLASMTDKYR Pal LH (SEQ ID NO. 98) 127 i1 KKLRAMTDKYR Pal LH (SEQ ID NO. 99) 128 i1 KKLRSATDKYRL Pal H (SEQ ID NO. 100) 129 i1 AGYQKKLRSMT Pal DKYRL (SEQ ID NO. 101) 130 i1 MAYQKKLRSMT Pal DKYRL (SEQ ID NO. 102) 131 i1 MGAQKKLRSMT Pal DKYRL (SEQ ID NO. 103) 132 i1 MGYAKKLRSMT Pal DKYRL (SEQ ID NO. 104) 133 i1 MGYQAKLRSMT Pal DKYRL (SEQ ID NO. 105) 134 i1 MGYQKALRSMT Pal DKYRL (SEQ ID NO. 106) 135 i1 MGYQKKARSMT Pal DKYRL (SEQ ID NO. 107) 136 i1 MGYQKKLASMT Pal DKYRL (SEQ ID NO. 108) 137 i1 KKLRSMTDKYR Myr LH (SEQ ID NO. 42) 138 i1 KKLRSMTDKYR Lca LH (SEQ ID NO. 42) 139 i1 KKLRSMADKYR Pal LH (SEQ ID NO. 109) 140 i1 KKLRSMTAKYR Pal LH (SEQ ID NO. 110) 141 i1 KKLRSMTDAYR Pal LH (SEQ ID NO. 111) 142 i1 KKLRSMTDKAR Pal LH (SEQ ID NO. 112) 143 i1 KKLRSMTDKYA Pal LH (SEQ ID NO. 113) 144 i1 KKLRSMTDKYR Pal AH (SEQ ID NO. 114) 145 i1 KKLRSMTDKYR Pal LA (SEQ ID NO. 115) 146 i1 MGYQKKLRAMT Pal DKYRL (SEQ ID NO. 116) 147 i1 MGYQKKLRSAT Pal DKYRL (SEQ ID NO.) 148 i1 MGYQKKLRSMA DKYRL (SEQ ID NO.) Pal 149 i1 MGYQKKLRSMT AKYRL (SEQ ID NO.) Pal 150 i1 MGYQKKLRSMT DAYRL (SEQ ID NO.) Pal 151 i1 MGYQKKLRSMT Pal DKARL(SEQ ID NO.) 152 i1 MGYQKKLRSMT Pal DKYAL (SEQ ID NO.) 153 i1 MGYQKKLRSMT Pal DKYRA (SEQ ID NO.) 154 i1 KKLRSMtDKYRL Pal H (SEQ ID NO.) 155 i1 KKLRSMTdKYRL Pal H (SEQ ID NO.) 156 i1 KKLRSMTDKYrL Pal H (SEQ ID NO.) 157 i1 KKLRSMTDKYRl Pal H (SEQ ID NO.) 158 i1 KKLRSMTDKYR Pal Lh (SEQ ID NO.) 159 i1 MGYQKKLRSMT Pal DKYR1 (SEQ ID NO.) 160 i1 MGYQKKLRSMT Pal DKYrL (SEQ ID NO.) 161 i1 MGYQKKLRSMT Pal DKyRL (SEQ ID NO.) 162 i1 MGYQKKLRSMT Pal DkYRL (SEQ ID NO.) 163 i1 MGYQKKLRSMT Pal dKYRL (SEQ ID NO.) 164 i1 MGYQKKLRSMt Pal DKYRL (SEQ ID NO.) 165 i1 mGYQKKLRSMT Pal DKYRL (SEQ ID NO.) 166 i1 MGyQKKLRSMT Pal DKYRL (SEQ ID NO.) 167 MGYqKKLRSMT Pal DKYRL (SEQ ID NO.) 168 i1 MGYQkKLRSMT Pal DKYRL (SEQ ID NO.) 169 i1 MGYQKkLRSMT Pal DKYRL (SEQ ID NO.) 170 i1 MGYQKKIRSMT Pal DKYRL (SEQ ID NO.) 171 i1 MGYQKKLISMT Pal DKYRL (SEQ ID NO.) 172 MGYQKKLRsMT Pal DKYRL (SEQ ID NO.) 173 i1 MGYQKKLRSmT Pal DKYRL (SEQ ID NO.) 174 i1 KKLRSMTDKYRl Pal S (SEQ ID NO.) 175 i1 MGYQKKLRSMT Pal DKYRL (SEQ ID NO.) 176 i1 MGYQKKLRSMT Elaidic DKYRL (SEQ ID NO.) 177 i1 MGYQKKLRSMT Oleic DKYRL (SEQ ID NO.) 178 i1 MGYQKKLRSMT 3- DKYRL (SEQ ID NO.) (dodecyloxy) propanoate 179 i1 MGYQKKLRSMT 16-hydroxy DKYRL (SEQ ID NO.) -Pal 180 i1 KKLRSMTDKYR Pal LH (SEQ ID NO. 42) 181 i1 KKLRSMTDKYR 3-(dodecyl LH (SEQ ID NO. 42) oxy)pro panoate 182 i1 KKLRSMTDKYR 16- LH (SEQ ID NO.42) hydroxy -Pal 183 i1 KKLRSMTDKYR LH ((SEQ ID NO. 42)) 184 i1 KKLRSMTDKYR LH (SEQ ID NO. 42) 185 i1 KKLRSMTDKYR LH (SEQ ID NO. 42) 186 i1 MGYQKKLRSMT DKYRL 187 i1 MGYQKKLRSMT DKYRL 188 i1 MGYQKKLRSMT DKYRL 189 i1 MGYQKKLRSpT Pal DKYRL 190 i1 MGYQKKLRpMT Pal DKYRL 191 i1 MGYQKKLpSMT Pal DKYRL 192 i1 MGYQKKpRSMT Pal DKYRL 193 i1 MGYQKKLRSMP Pal DKYRL 194 i1   XGYQKKRLSXT C₁₅H₃₁ DKYRL  (CO) X = noreleucine

TABLE 7 CXCR4 it loop compound structures Comp. # Structure  1

 2

 3

 4

 5

 6

 7

 8

 9

 10

 11

 12

 13

 14

 15

 16

 17

 18

 19

 20

 21

 22

 23

 24

 25

 26

 27

 28

 29

 30

 31

 32

 33

 34

 35

 36

 37

 38

 39

 40

 41

 42

 43

 44

 45

 46

 47

 48

 49

 50

 51

 52

 53

 54

 55

 56

 58

 59

 60

 61

 62

 63

 64

 65

 66

 67

 68

 69

 70

 71

 72

 73

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

TABLE 8  CXCR4 i2 loop compounds Comp. # Loop Sequence Lipid MW Comments 74 i2 DRYLAIVHATNSQRPR Pal 2713.439 Dual Lipid KLL (SEQ. ID NO), 75 i2 VHATNSQRPRKLLAEK Pal 2446.974 VVY (SEQ. ID NO), 76 i2 DRYLAIVHATNSQRPR Myr 2742.438 second KLL (SEQ. ID NO), lipid on backbone 77 i2 DRYLAIVHATNSQRPR Pal 2489.014 KLL (SEQ. ID NO), 78 i2 VHATNSQRPRKLLA Pal 1828.253 (SEQ. ID NO), 79 i2 HATNSQRPRKL (SEQ. Pal 1544.886 ID NO), 80 i2 HATNSQRPRKLLA Pal 1729.121 (SEQ. ID NO), 81 i2 HATNSQRPRKLLAE Pal 1858.235 (SEQ. ID NO), 82 i2 HATNSQRPRKLLAEK Pal 1986.408 (SEQ. ID NO), 83 i2 HATNSQRPRKLLAEKV Pal 2085.539 (SEQ. ID NO),

TABLE 9 CXCR4 i2 loop compound structures Comp. # Structure 74

75

76

77

78

79

80

81

82

83

TABLE 10  CXCR4 i3 loop compounds Loop Sequence Lipid Comments MW 84 i3 HSKKGHQKRKALK Pal 1783.258 (SEQ. ID NO) 85 i3 HSKGHQKRKALK Pal 1655.086 (SEQ. ID NO 369) 87 i3 HSKGHQKRKQALK C16H33 Pentadecyl- 1924.449 (SEQ ID NO.) alanine with Biotin 88 i3 SKLSHSKGHQKRKAL Pal 2598.225 KTTVIL (SEQ ID NO.) 89 i3 KLSHSKGHQKRKALK Pal 2511.147 TTVIL (SEQ ID NO.) 90 i3 KLSHSKGHQKRKALK Pal 2284.832 TTV (SEQ ID NO.) 91 i3 KLSHSKGHQKRKALK Pal 2084.597 T(SEQ ID NO.) 92 i3 KLSHSKGHQKRKALK Pal 1983.493 (SEQ ID NO.) 93 i3 KLSHSKGHQKRKAL Pal 1855.321 (SEQ ID NO.) 94 i3 KLSHSKGHQKRKA Pal 1742.163 (SEQ ID NO.) 95 i3 LSHSKGHQKRKALK Pal 1855.321 (SEQ ID NO.) 96 i3 SHSKGHQKRKALK Pal 1742.163 (SEQ ID NO.) 97 i3 HSKGHQKRKALKT Pal 1756.19 (SEQ ID NO.) 98 i3 HSKGHQKRKALKTT Pal 1857.294 (SEQ ID NO.) 99 i3 HSKGHQKRKALKTTV Pal 1956.425 (SEQ ID NO.) 100 i3 HSKGHQKRKALKTTV Pal 2069.583 I (SEQ ID NO.) 101 i3 SKLSHSKGHQKRKAL Pal 2070.571 K (SEQ ID NO.) 102 i3 IIISKLSHSKGHQKRKA Pal 2511.147 LKT (SEQ ID NO.) 103 i3 IIISKLSHSKGHQKRKA myr dula lipid, 2765.556 LKT (SEQ ID NO.) backbone 104 i3 IIISKLSHSKGHQKRKA Pal dual lipid 2735.573 LKT (SEQ ID NO.) 105 i3 KLSHSKGHQKRKALK Myr Dual lipid, 2764.571 TTVIL (SEQ ID No.) backbone 106 i3 QHLHIALKKSTSRKVK Pal scrambled 2598.225 SGTLK (SEQ ID No.) ATI2357

TABLE 11 CXCR4 i3 loop compound structures Comp. # Structure 106

105

104

103

102

101

100

99

98

97

96

95

94

93

92

91

90

89

88

87

85

84

TABLE 12 CXCR4 i4 loop compounds No. Loop Sequence Lipid MW Comments 107 i4 GAKFKTSAQHALTS Myr 4248.067 Backbone VSRGSSLKILSKGKR lipid-dual GGHSSVST lipid (SEQ ID NO.) 108 i4 GAKFKTSAQHALTS Myr 3592.41 N-terminus VSRGSSLKILSKGKR and back- G (SEQ ID NO.) bone lipid 109 i4 GAKFKTSAQHALTS VSRGSSLKILSKGKR Pal 3994.644 GGHSSVST (SEQ ID NO.) 110 i4 GAKFKTSAQHALTS Pal 3870.571 VSRGSSLKILSKGKR GGSCFH (SEQ ID NO.) 111 i4 GAKFKTSAQHALTS Pal 3338.987 VSRGSSLKILSKGKR G (SEQ ID NO.) 112 i4 GAKFKTSAQHALTS Pal 3052.8 VSRGSSLKILSGGK (SEQ ID NO.) 113 i4 GAKFKTSAQHALTS Pal 2083.477 VSRG (SEQ ID NO.) 114 i4 GAKFKTSAQHALTS Pal 2940.526 VSRGSSLKILSK (SEQ ID NO.) 115 i4 GAKFKTSAQHALTS Pal 2498.961 VSRGSSLK (SEQ ID NO.) 116 i4 GAKFKTSAQHALTS Pal 1938.18 VR (SEQ ID NO.)

TABLE 13 CXCR4 i4 loop compound structures Comp. # Structure 107

108

109

110

111

112

113

114

115

116

In a thirteenth aspect, the compounds are selected from:

or a pharmaceutically acceptable salt of any of the foregoing.

“Cycloalkyl” used alone or as part of a larger moiety such as “cycloalkylalkyl” refers to a monocyclic or polycyclic, non-aromatic ring system of 3 to 20 carbon atoms, 3 to 12 carbon atoms, or 3 to 9 carbon atoms, which may be saturated or unsaturated. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cyclohexa-1,3-dienyl, cyclooctyl, cycloheptanyl, norbornyl, adamantyl, and the like.

“Heterocycloalkyl” refers to a saturated or unsaturated, non-aromatic, monocyclic or polycyclic ring system of 3 to 20 atoms, 3 to 12 atoms, or 3 to 8 atoms, containing one to four ring heteroatoms chosen from O, N and S. Examples of heterocyclyl groups include pyrrolidine, piperidine, tetrahydrofuran, tetrahydropyran, tetrahydrothiophene, tetrahydrothiopyran, isoxazolidine, 1,3-dioxolane, 1,3-dithiolane, 1,3-dioxane, 1,4-dioxane, 1,3-dithiane, 1,4-dithiane, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydro-2H-1,2-thiazine-1,1-dioxide, isothiazolidine-1,1-dioxide, pyrrolidin-2-one, piperidin-2-one, piperazin-2-one, and morpholin-2-one, and the like.

“Halogen” and “halo” refer to fluoro, chloro, bromo or iodo.

“Haloalkyl” refers to an alkyl group substituted with one or more halogen atoms. By analogy, “haloalkenyl”, “haloalkynyl”, etc., refers to the group (for example alkenyl or alkynyl) substituted by one or more halogen atomes.

“Cyano” refers to the group —CN.

“Oxo” refers to a divalent ═O group.

“Thioxo” refers to a divalent ═S group.

“Ph” refers to a phenyl group.

“Carbonyl” refers to a divalent —C(O)— group.

“Alkyl” used alone or as part of a larger moiety such as “hydroxyalkyl”, “alkoxyalkyl”, “alkylamine” refers to a straight or branched, saturated aliphatic group having the specified number of carbons, typically having 1 to 12 carbon atoms. More particularly, the aliphatic group may have 1 to 10, 1 to 8, 1 to 6, or 1 to 4 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl, and the like.

“Alkenyl” refers to a straight or branched aliphatic group with at least one double bond. Typically, alkenyl groups have from 2 to 12 carbon atoms, from 2 to 8, from 2 to 6, or from 2 to 4 carbon atoms. Examples of alkenyl groups include ethenyl (—CH═CH₂), n-2-propenyl (allyl, —CH₂CH═CH₂), pentenyl, hexenyl, and the like.

“Alkynyl” refers to a straight or branched aliphatic group having at least 1 site of alkynyl unsaturation. Typically, alkynyl groups contain 2 to 12, 2 to 8, 2 to 6 or 2 to 4 carbon atoms. Examples of alkynyl groups include ethynyl (—C≡CH), propargyl (—CH₂C≡CH), pentynyl, hexynyl, and the like.

“Alkylene” refers to a bivalent saturated straight-chained hydrocarbon, e.g., C₁-C₆ alkylene includes —(CH₂)₆—, —CH₂—CH—(CH₂)₃CH₃, and the like. “Bivalent means that the alkylene group is attached to the remainder of the molecule through two different carbon atoms.

“Alkenylene” refers to an alkylene group with in which one carbon-carbon single bond is replaced with a double bond.

“Alkynylene” refers to an alkylene group with in which one carbon-carbon single bond is replaced with a triple bond.

“Aryl” used alone or as part of a larger moiety as in “aralkyl” refers to an aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring or multiple condensed rings. The term “aryl” also includes aromatic carbocycle(s) fused to cycloalkyl or heterocycloalkyl groups. Examples of aryl groups include phenyl, benzo[d][1,3]dioxole, naphthyl, phenantrenyl, and the like.

“Aryloxy” refers to an —OAr group, wherein 0 is an oxygen atom and Ar is an aryl group as defined above.

“Aralkyl” refers to an alkyl having at least one alkyl hydrogen atom replaced with an aryl moiety, such as benzyl, —(CH₂)₂phenyl, —(CH₂)₃phenyl, —CH(phenyl)₂, and the like.

“Alkyl cycloalkyl” refers to an alkyl having at least one alkyl hydrogen atom replaced with a cycloalkyl moiety, such as —CH₂-cyclohexyl, —CH₂-cyclohexenyl, and the like.

“Heteroaryl” used alone or a part of a larger moiety as in “heteroaralkyl” refers to a 5 to 14 membered monocyclic, bicyclic or tricyclic heteroaromatic ring system, containing one to four ring heteroatoms independently selected from nitrogen, oxygen and sulfur. The term “heteroaryl” also includes heteroaromatic ring(s) fused to cycloalkyl or heterocycloalkyl groups. Particular examples of heteroaryl groups include optionally substituted pyridyl, pyrrolyl, pyrimidinyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,3,4-triazinyl, 1,2,3-triazinyl, benzofuryl, [2,3-dihydro]benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, isobenzothienyl, indolyl, isoindolyl, 3H-indolyl, benzimidazolyl, imidazo[1,2-a]pyridyl, benzothiazolyl, benzoxa-zolyl, quinolizinyl, quinazolinyl, pthalazinyl, quinoxalinyl, cinnolinyl, napthyridinyl, pyrido[3,4-b]pyridyl, pyrido[3,2-b]pyridyl, pyrido[4,3-b]pyridyl, quinolyl, isoquinolyl, tetrazolyl, 1,2,3,4-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl, purinyl, pteridinyl, carbazolyl, xanthenyl, benzoquinolyl, and the like.

“Heteroaryloxy” refers to an —OHet group, wherein O is an oxygen atom and Het is a heteroaryl group as defined above.

“Heteroaralkyl” refers to an alkyl having at least one alkyl hydrogen atom replaced with a heteroaryl moiety, such as —CH₂-pyridinyl, —CH₂-pyrimidinyl, and the like.

“Alkoxy” refers to the group —O—R where R is “alkyl”, “cycloalkyl”, “alkenyl”, or “alkynyl”. Examples of alkoxy groups include for example, methoxy, ethoxy, ethenoxy, and the like.

“Alkyl heterocycloalkyl” refers to an alkyl having at least one alkyl hydrogen atom replaced with a heterocycloalkyl moiety, such as —CH₂-morpholino, —CH₂-piperidyl and the like.

“Alkoxycarbonyl” refers to the group —C(O)OR where R is “alkyl”, “alkenyl”, “alkynyl”, “cycloalkyl”, “heterocycloalkyl”, “aryl”, or “heteroaryl”.

“Hydroxyalkyl” and “alkoxyalkyl” are alky groups substituted with hydroxyl and alkoxy, respectively.

“Amino” means —NH₂; “alkylamine” and “dialkylamine” mean —NHR and —NR₂, respectively, wherein R is an alkyl group. “Cycloalkylamine” and “dicycloalkylamine” mean —NHR and —NR₂, respectively, wherein R is a cycloalkyl group. “Cycloalkylalkylamine” means —NHR wherein R is a cycloalkylalkyl group. “[Cycloalkylalkyl][alkyl]amine” means —N(R)₂ wherein one R is cycloalkylalkyl and the other R is alkyl.

Haloalkyl and halocycloalkyl include mono, poly, and perhaloalkyl groups where the halogens are independently selected from fluorine, chlorine, bromine and iodine.

Suitable substituents for “alkyl”, “alkenyl”, “alkynyl”, “cycloalkyl”, “heterocycloalkyl”, “aryl”, or “heteroaryl”, etc., are those which will form a stable compound of the invention. Examples of suitable substituents are those selected from the group consisting of halogen, —CN, —OH, —NH₂, (C₁-C₄)alkyl, (C₁-C₄)haloalkyl, aryl, heteroaryl, (C₃-C₇)cycloalkyl, (5-7 membered) heterocycloalkyl, —NH(C₁-C₆)alkyl, —N((C₁-C₆)alkyl)₂, (C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl, —CONH₂, —OCONH₂, —NHCONH₂, —N(C₁-C₆)alkylCONH₂, —N(C₁-C₆)alkylCONH(C₁-C₆)alkyl, —NHCONH(C₁-C₆)alkyl, —NHCON((C₁-C₆)alkyl)₂, —N(C₁-C₆)alkylCON((C₁-C₆)alkyl)₂, —NHC(S)NH₂, —N(C₁-C₆)alkylC(S)NH₂, —N(C₁-C₆)alkylC(S)NH(C₁-C₆)alkyl, —NHC(S)NH(C₁-C₆)alkyl, —NHC(S)N((C₁-C₆)alkyl)₂, —N(C₁-C₆)alkylC(S)N((C₁-C₆)alkyl)₂, —CONH(C₁-C₆)alkyl, —OCONH(C₁-C₆)alkyl —CON((C₁-C₆)alkyl)₂, —C(S)(C₁-C₆)alkyl, —S(O)_(p)(C₁-C₆)alkyl, —S(O)_(p)NH₂, —S(O)_(p)NH(C₁-C₆)alkyl, —S(O)_(p)N((C₁-C₆)alkyl)₂, —CO(C₁-C₆)alkyl, —OCO(C₁-C₆)alkyl, —C(O)O(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —C(O)H or —CO₂H. More particularly, the substituents are selected from halogen, —CN, —OH, —NH₂, (C₁-C₄)alkyl, (C₁-C₄)haloalkyl, (C₁-C₄)alkoxy, phenyl, and (C₃-C₇)cycloalkyl. Within the framework of this invention, said “substitution” is also meant to encompass situations where a hydrogen atom is replaced with a deuterium atom. p is an integer with a value of 1 or 2.

Pharmaceutically acceptable salts of the compounds disclosed herein are included in the present invention. For example, an acid salt of a compound containing an amine or other basic group can be obtained by reacting the compound with a suitable organic or inorganic acid, resulting in pharmaceutically acceptable anionic salt forms. Examples of anionic salts include the acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, glyceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate, pamoate, pantothenate, phosphate/diphospate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate, tosylate, and triethiodide salts.

Salts of the compounds containing an acidic functional group can be prepared by reacting with a suitable base. Such a pharmaceutically acceptable salt can be made with a base which affords a pharmaceutically acceptable cation, which includes alkali metal salts (especially sodium and potassium), alkaline earth metal salts (especially calcium and magnesium), aluminum salts and ammonium salts, as well as salts made from physiologically acceptable organic bases such as trimethylamine, triethylamine, morpholine, pyridine, piperidine, picoline, dicyclohexylamine, N,N′-dibenzylethylenediamine, 2-hydroxyethylamine, bis-(2-hydroxyethyl)amine, tri-(2-hydroxyethyl)amine, procaine, dibenzylpiperidine, dehydroabietylamine, N,N′-bisdehydroabietylamine, glucamine, N-methylglucamine, collidine, quinine, quinoline, and basic amino acids such as lysine and arginine.

Pharmaceutical Compositions

The invention also provides pharmaceutical compositions comprising an effective amount of a compound Formula I (e.g., including any of the formulae herein), or a pharmaceutically acceptable salt of said compound; and a pharmaceutically acceptable carrier. The carrier(s) are “pharmaceuticallyacceptable” in that they are not deleterious to the recipient thereof in an amount used in the medicament.

Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

If required, the solubility and bioavailability of the compounds of the present invention in pharmaceutical compositions may be enhanced by methods well-known in the art. One method includes the use of lipid excipients in the formulation. See “Oral Lipid-Based Formulations: Enhancing the Bioavailability of Poorly Water-Soluble Drugs (Drugs and the Pharmaceutical Sciences),” David J. Hauss, ed. Informa Healthcare, 2007; and “Role of Lipid Excipients in Modifying Oral and Parenteral Drug Delivery: Basic Principles and Biological Examples,” Kishor M. Wasan, ed. Wiley-Interscience, 2006.

Another known method of enhancing bioavailability is the use of an amorphous form of a compound of this invention optionally formulated with a poloxamer, such as LUTROL™ and PLURONIC™ (BASF Corporation), or block copolymers of ethylene oxide and propylene oxide. See U.S. Pat. No. 7,014,866; and United States patent publications 20060094744 and 20060079502.

The pharmaceutical compositions of the invention include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), pulmonary, vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration. In certain embodiments, the compound of the formulae herein is administered transdermally (e.g., using a transdermal patch or iontophoretic techniques). Other formulations may conveniently be presented in unit dosage form, e.g., tablets, sustained release capsules, and in liposomes, and may be prepared by any methods well known in the art of pharmacy. See, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, Pa. (17th ed. 1985).

Such preparative methods include the step of bringing into association with the molecule to be administered ingredients such as the carrier that constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers, liposomes or finely divided solid carriers, or both, and then, if necessary, shaping the product.

In certain embodiments, the compound is administered orally. Compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, sachets, or tablets each containing a predetermined amount of the active ingredient; a powder or granules; a solution or a suspension in an aqueous liquid or a non-aqueous liquid; an oil-in-water liquid emulsion; a water-in-oil liquid emulsion; packed in liposomes; or as a bolus, etc. Soft gelatin capsules can be useful for containing such suspensions, which may beneficially increase the rate of compound absorption.

In the case of tablets for oral use, carriers that are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.

Compositions suitable for oral administration include lozenges comprising the ingredients in a flavored basis, usually sucrose and acacia or tragacanth; and pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia.

Compositions suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampules and vials, and may be stored in a freeze dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.

Such injection solutions may be in the form, for example, of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant.

The pharmaceutical compositions of this invention may be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing a compound of this invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions of this invention may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art. See, e.g.: Rabinowitz J D and Zaffaroni A C, U.S. Pat. No. 6,803,031, assigned to Alexza Molecular Delivery Corporation.

Topical administration of the pharmaceutical compositions of this invention is especially useful when the desired treatment involves areas or organs readily accessible by topical application. For topical application topically to the skin, the pharmaceutical composition should be formulated with a suitable ointment containing the active components suspended or dissolved in a carrier. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax, and water. Alternatively, the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water. The pharmaceutical compositions of this invention may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Topically-transdermal patches and iontophoretic administration are also included in this invention.

Application of the patient therapeutics may be local, so as to be administered at the site of interest. Various techniques can be used for providing the patient compositions at the site of interest, such as injection, use of catheters, trocars, projectiles, pluronic gel, stents, sustained drug release polymers or other device which provides for internal access.

Thus, according to yet another embodiment, the compounds of this invention may be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents, or catheters. Suitable coatings and the general preparation of coated implantable devices are known in the art and are exemplified in U.S. Pat. Nos. 6,099,562; 5,886,026; and 5,304,121. The coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coatings may optionally be further covered by a suitable topcoat of fluorosilicone, polysaccharides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics in the composition. Coatings for invasive devices are to be included within the definition of pharmaceutically acceptable carrier, adjuvant or vehicle, as those terms are used herein.

According to another embodiment, the invention provides a method of coating an implantable medical device comprising the step of contacting said device with the coating composition described above. It will be obvious to those skilled in the art that the coating of the device will occur prior to implantation into a mammal.

According to another embodiment, the invention provides a method of impregnating an implantable drug release device comprising the step of contacting said drug release device with a compound or composition of this invention. Implantable drug release devices include, but are not limited to, biodegradable polymer capsules or bullets, non-degradable, diffusible polymer capsules and biodegradable polymer wafers.

According to another embodiment, the invention provides an implantable medical device coated with a compound or a composition comprising a compound of this invention, such that said compound is therapeutically active.

According to another embodiment, the invention provides an implantable drug release device impregnated with or containing a compound or a composition comprising a compound of this invention, such that said compound is released from said device and is therapeutically active.

Where an organ or tissue is accessible because of removal from the patient, such organ or tissue may be bathed in a medium containing a composition of this invention, a composition of this invention may be painted onto the organ, or a composition of this invention may be applied in any other convenient way.

In another embodiment, a composition of this invention further comprises a second therapeutic agent. In one embodiment, the second therapeutic agent is one or more additional compounds of the invention.

In another embodiment, the second therapeutic agent may be selected from any compound or therapeutic agent known to have or that demonstrates advantageous properties when administered with a compound having the same mechanism of action as the CXCR4 receptor compound of Formula I.

In a particular embodiment, the second therapeutic is an agent useful in the treatment or prevention of a disease or condition selected from, bone marrow transplantation, chemosensitization, cancer, metastatic disease (e.g., cancer), inflammatory diseases, HIV infection and stem cell-based regenerative medicine, bone marrow transplantation, chemosensitization, cancer, metastatic disease (e.g., cancer), inflammatory diseases, HIV infection and stem cell-based regenerative medicine. For example, the second therapeutic agent is an agent useful in improving the quanity and quality of stem cell harvesting prior to bone marrow ablative cancer therapy.

For example, the second therapeutic agent can be selected from: G-CSF (granulocyte colony-stimulating factor), cyclophosphamide, rituximab and fludaraine. In a particular embodiment, the second therapeutic agent is G-CSF.

In one embodiment, the invention provides separate dosage forms of a compound of this invention and one or more of any of the above-described second therapeutic agents, wherein the compound and second therapeutic agent are associated with one another. The term “associated with one another” as used herein means that the separate dosage forms are packaged together or otherwise attached to one another such that it is readily apparent that the separate dosage forms are intended to be sold and administered together (within less than 24 hours of one another, consecutively or simultaneously).

In the pharmaceutical compositions of the invention, the compound of the present invention is present in an effective amount. As used herein, the term “effective amount” refers to an amount which, when administered in a proper dosing regimen, is sufficient to treat (therapeutically or prophylactically) the target disorder. For example, and effective amount is sufficient to reduce or ameliorate the severity, duration or progression of the disorder being treated, prevent the advancement of the disorder being treated, cause the regression of the disorder being treated, or enhance or improve the prophylactic or therapeutic effect(s) of another therapy. Preferably, the compound is present in the composition in an amount of from 0.1 to 50 wt. %, more preferably from 1 to 30 wt. %, most preferably from 5 to 20 wt. %.

The interrelationship of dosages for animals and humans (based on milligrams per meter squared of body surface) is described in Freireich et al., (1966) Cancer Chemother. Rep 50: 219. Body surface area may be approximately determined from height and weight of the patient. See, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, N.Y., 1970, 537.

For pharmaceutical compositions that comprise a second therapeutic agent, an effective amount of the second therapeutic agent is between about 20% and 100% of the dosage normally utilized in a monotherapy regime using just that agent. Preferably, an effective amount is between about 70% and 100% of the normal monotherapeutic dose. The normal monotherapeutic dosages of these second therapeutic agents are well known in the art. See, e.g., Wells et al., eds., Pharmacotherapy Handbook, 2nd Edition, Appleton and Lange, Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda, Calif. (2000), each of which references are incorporated herein by reference in their entirety.

The compounds for use in the method of the invention can be formulated in unit dosage form. The term “unit dosage form” refers to physically discrete units suitable as unitary dosage for subjects undergoing treatment, with each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, optionally in association with a suitable pharmaceutical carrier. The unit dosage form can be for a single daily treatment dose or one of multiple daily treatment doses (e.g., about 1 to 4 or more times per day). When multiple daily treatment doses are used, the unit dosage form can be the same or different for each dose.

Methods of Treatment

As used herein the term “subject” and “patient” typically means a human, but can also be an animal in need of treatment, e.g., companion animals (dogs, cats, and the like), farm animals (cows, pigs, horses, sheep, goats, and the like) and laboratory animals (rats, mice, guinea pigs, and the like).

The terms “treat” and “treating” are used interchangeably and include both therapeutic treatment and prophylactic treatment (reducing the likelihood of development). Both terms mean decrease, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a disease (e.g., a disease or disorder delineated herein), lessen the severity of the disease or improve the symptoms associated with the disease.

“Disease” means any condition or disorder that damages or interferes with the normal function of a cell, tissue, or organ.

As used herein, the term “effective amount” refers to an amount which, when administered in a proper dosing regimen, is sufficient to treat (therapeutically or prophylactically) the target disorder. For example, and effective amount is sufficient to reduce or ameliorate the severity, duration or progression of the disorder being treated, prevent the advancement of the disorder being treated, cause the regression of the disorder being treated, or enhance or improve the prophylactic or therapeutic effect(s) of another therapy.

The invention also includes methods of treating diseases, disorders or pathological conditions which benefit from modulation of the CXCR4 receptor comprising administering an effective amount of a CXCR4 receptor compound of the invention to a subject in need thereof. Diseases and conditions which can benefit from modulation (inhibition or activation) of the CXCR4 receptor include, but are not limited to, bone marrow transplantation, chemosensitization, cancer, metastatic disease (e.g., cancer), inflammatory diseases, HIV infection and stem cell-based regenerative medicine. For example, improving the quanity and quality of stem cell harvesting prior to bone marrow ablative cancer therapy.

Bone marrow transplantation can be for treatment of hematological and non hematological malignancies, phagocyte disorders, anemias and myeloproliferative disorders, amyloidoses, radiation poisoning, congenital lysosomal storage disorders and congenital immunodefficiencies.

CXCR4 antagonists are useful for autologous and allogeneic hematopoietic stem cell transplantation (HSCT) to treat acquired as well as congenital diseases. CXCR4 antagonist will be injected into the patients (autologous HSCT) or healthy HLA-matched donor (allogeneic HSCT) before the HSCT procedure. Injection the CXCR4 antagonist induces mobilization of hematopoietc stem cells from bone marrow niche into the peripheral blood. Treatment with the novel CXCR4 antagonist will increase the yield of peripheral hematopoietic stem cells in the amount sufficient for their successful reengraftment or long term storage. HSCs collected during the apheresis procedure will be further reinfused into the patient undergoing HSCT.

The CXCR4 receptor compounds of the invention having antagonist activity are also useful for chemosensitization treatment of patients with hematological malignancies. These patients will be treated with CXCR4 antagonist to induce egress of malignant white blood cells from hematopoietic organs into peripheral circulation. As a result, these abnormal cells will be more readily targeted by chemotherapeutic agents administered intravenously. b

Accumulated preclinical data suggests that CXCR4 is essential for the development and progression of inflammatory diseases including but not limited to rheumatoid arthritis and inflammatory bowl disease. Therefore antagonism of CXCR4 can be beneficial for the patients suffering from these disorders. CXCR4 is also a coreceptor for the entry of several HIV-1 strains. Pharmacological targeting of CXCR4-dependent can potentially modulate HIV-1 tropism and it's infectivity.

In one embodiment, an effective amount of a compound of this invention can range from about 0.005 mg to about 5000 mg per treatment. In more specific embodiments, the range is from about 0.05 mg to about 1000 mg, or from about 0.5 mg to about 500 mg, or from about 5 mg to about 50 mg. Treatment can be administered one or more times per day (for example, once per day, twice per day, three times per day, four times per day, five times per day, etc.). When multiple treatments are used, the amount can be the same or different.

It is understood that a treatment can be administered every day, every other day, every 2 days, every 3 days, every 4 days, every 5 days, etc. For example, with every other day administration, a treatment dose can be initiated on Monday with a first subsequent treatment administered on Wednesday, a second subsequent treatment administered on Friday, etc. Treatment is typically administered from one to two times daily. Effective doses will also vary, as recognized by those skilled in the art, depending on the diseases treated, the severity of the disease, the route of administration, the sex, age and general health condition of the patient, excipient usage, the possibility of co-usage with other therapeutic treatments such as use of other agents and the judgment of the treating physician.

Alternatively, the effective amount of a compound of the invention is from about 0.01 mg/kg/day to about 1000 mg/kg/day, from about 0.1 mg/kg/day to about 100 mg/kg/day, from about 0.5 mg/kg/day to about 50 mg/kg/day, or from about 1 mg/kg/day to 10 mg/kg/day.

In another embodiment, any of the above methods of treatment comprises the further step of co-administering to said patient one or more second therapeutic agents. The choice of second therapeutic agent may be made from any second therapeutic agent known to be useful for co-administration with a compound that modulates the CXCR4 receptor. The choice of second therapeutic agent is also dependent upon the particular disease or condition to be treated. Examples of second therapeutic agents that may be employed in the methods of this invention are those set forth above for use in combination compositions comprising a compound of this invention and a second therapeutic agent.

The term “co-administered” as used herein means that the second therapeutic agent may be administered together with a compound of this invention as part of a single dosage form (such as a composition of this invention comprising a compound of the invention and an second therapeutic agent as described above) or as separate, multiple dosage forms. Alternatively, the additional agent may be administered prior to, consecutively with, or following the administration of a compound of this invention. In such combination therapy treatment, both the compounds of this invention and the second therapeutic agent(s) are administered by conventional methods. The administration of a composition of this invention, comprising both a compound of the invention and a second therapeutic agent, to a subject does not preclude the separate administration of that same therapeutic agent, any other second therapeutic agent or any compound of this invention to said subject at another time during a course of treatment.

In one embodiment of the invention, where a second therapeutic agent is administered to a subject, the effective amount of the compound of this invention is less than its effective amount would be where the second therapeutic agent is not administered. In another embodiment, the effective amount of the second therapeutic agent is less than its effective amount would be where the compound of this invention is not administered. In this way, undesired side effects associated with high doses of either agent may be minimized. Other potential advantages (including without limitation improved dosing regimens and/or reduced drug cost) will be apparent to those of skill in the art.

Kits

The present invention also provides kits for use to treat the target disease, disorder or condition. These kits comprise (a) a pharmaceutical composition comprising a compound of Formula I, or a salt thereof, wherein said pharmaceutical composition is in a container; and (b) instructions describing a method of using the pharmaceutical composition to treat the target disease, disorder or condition.

The container may be any vessel or other sealed or sealable apparatus that can hold said pharmaceutical composition. Examples include bottles, ampules, divided or multi-chambered holders bottles, wherein each division or chamber comprises a single dose of said composition, a divided foil packet wherein each division comprises a single dose of said composition, or a dispenser that dispenses single doses of said composition. The container can be in any conventional shape or form as known in the art which is made of a pharmaceutically acceptable material, for example a paper or cardboard box, a glass or plastic bottle or jar, a re-sealable bag (for example, to hold a “refill” of tablets for placement into a different container), or a blister pack with individual doses for pressing out of the pack according to a therapeutic schedule. The container employed can depend on the exact dosage form involved, for example a conventional cardboard box would not generally be used to hold a liquid suspension. It is feasible that more than one container can be used together in a single package to market a single dosage form. For example, tablets may be contained in a bottle, which is in turn contained within a box. In one embodiment, the container is a blister pack.

The kits of this invention may also comprise a device to administer or to measure out a unit dose of the pharmaceutical composition. Such device may include an inhaler if said composition is an inhalable composition; a syringe and needle if said composition is an injectable composition; a syringe, spoon, pump, or a vessel with or without volume markings if said composition is an oral liquid composition; or any other measuring or delivery device appropriate to the dosage formulation of the composition present in the kit.

In certain embodiment, the kits of this invention may comprise in a separate vessel of container a pharmaceutical composition comprising a second therapeutic agent, such as one of those listed above for use for co-administration with a compound of this invention.

General Methods for Preparing CXCR4 Receptor Compounds Synthesis of Peptides

The peptide component (P) of the compounds of the invention can be synthesized by incorporating orthogonally protected amino acids in a step-wise fashion. Any suitable synthetic methods can be used. Traditional Fmoc or Boc chemistry can be easily adapted to provide the desired peptide component (P) of the compounds of the invention. Fmoc is generally preferred, because the cleavage of the Fmoc protecting group is milder than the acid deprotection required for Boc cleavage, which requires repetitive acidic deprotections that lead to alteration of sensitive residues, and increase acid catalyzed side reactions. (G. B. FIELDS et al. in Int. J. Pept. Protein, 1990, 35, 161).

The peptides can be assembled linearly via Solid Phase Peptide Synthesis (SPPS), can be assembled in solution using modular condensations of protected or unprotected peptide components or a combination of both.

Solid Phase Peptide Synthesis

For SPPS, an appropriate resin is chosen that will afford the desired moiety on the C-terminus upon cleavage. For example upon cleavage of the linear peptide, a Rink amide resin will provide a primary amide on the C-terminus, whereas a Rink acid resin will provide an acid. Rink acid resins are more labile than Rink amide resins and the protected peptide could also be cleaved and subsequently the free acid activated to react with amines or other nucleophiles. Alternatively, other resins could provide attachment of other moieties prior to acylation, leading to cleavage of an alkylated secondary amide, ester or other desired C-terminal modification. A review of commonly used resins and the functional moiety that results after cleavage can be found in manufacturer literature such as NovaBiochem or Advanced Chemtech catalogues.

Typically a resin is chosen such that after cleavage the C-terminus is an amide bond. Rink amide resin is a resin that results in a C-terminal amide during cleavage. The orthogonally protected Fmoc amino acids are added stepwise using methods well known in literature (Bodansky M. Principles of Peptide synthesis (1993) 318p; Peptide Chemistry, a Practical Textbook (1993); Spinger-Verlag). These procedures could be done manually or by using automated peptide synthesizers.

The process involves activating the acid moiety of a protected amino acid, using activating agents such as HBTU, HATU, PyBop or simple carbodiimides. Often an additive is used to decrease racemization during coupling such as HOBt or HOAt (M. SCHNÖLZER et al., Int. J. Pept. Protein Res., 1992, 40, 180). Manually, the coupling efficiency can be determined photometrically using a ninhydrin assay. If the coupling efficiency is below 98%, a second coupling may be desired. After the second coupling a capping step may be employed to prevent long deletion sequences to form, simplifying the purification of the desired final compound. With automation, second couplings are not commonly required, unless a residue is known to be problematic such as Arginine.

Deprotection of the Fmoc is most commonly accomplished using piperidine (20%) in dimethylformamide (DMF). Alternatively other secondary amines may also be used such as morpholine, diethylamine or piperazine. This reaction is facile and normally is accomplished within 20 minutes using piperidine. After deprotection the resin is washed several times with DMF and DCM prior to coupling with the next residue. This process is repeated, assembling the peptide linearly until the sequence is complete. The final Fmoc is removed, which allows for coupling with the tether moiety.

In a preferred synthesis, the peptide is formed by SPPS accomplished manually or in an automated fashion using a commercially available synthesizer such as the CEM Microwave peptide synthesizer, Rainin Symphony synthesizer, or ABI 433 flow-through synthesizer. Commercially available Rink Amide resin is used for synthesizing the C-terminal amide peptides (Rink, H. Tetrahedron Lett, 28, 4645, 1967). Peptide synthesis reagents (coupling, deprotection agents) are commercially available and include HOBT, HBTU (Novabiochem) as well as DMF, DCM, Piperidine, NMP, and DIEA (Sigma-Aldrich). Suitably protected amino acids for use in solid phase peptide synthesis are commercially available from many sources, including Sigma-Aldrich and CEM Corporation.

For example, a convenient preparation of peptides on a 0.1 mmol or 0.25 mmol scale uses Rink amide solid-phase resin with a substitution of about 0.6 mmol/g. Linear attachment of the amino acids is accomplished on a ABI continuous flow automated synthesizer using 5 eq of orthogonally protected amino acid (AA), and using HBTU/HOBt coupling protocol, (5 eq. of each reagent). In another preferred synthesis, peptides can be synthesized using a microwave instrument using 10 eq of reagents. Deprotection of Fmoc can be accomplished with 20% piperidine in DMF followed by washing with DMF and DCM.

In both cases (i.e., Rink acid and Rink amide resins), final Fmoc deprotection of the N-terminus would leave a free amine after cleavage from the resin unless it is modified prior to cleavage. In the compounds of the invention, tether moieties are attached through amide bonds.

Solution Phase Synthesis of Peptides

For solution phase synthesis the desired peptide is generally broken down into peptide fragments in units of 2-4 amino acids. The selected unit is dependent on the sequence, the stability of the fragment to racemization, and the ease of assembly. As each amino acid is added, only 1-1.5 eq of the residue is required, versus the 5-10 equivalents of reagent required for SSPS. Preactivated amino acids such as OSu active ester and acid fluorides also can be used, requiring only a base for completion of the reaction.

Coupling times require 1.5-2 hours for each step. Two fragments are condensed in solution, giving a larger fragment that then can be further condensed with additional fragments until the desired sequence is complete. The solution phase protocol uses only 1 eq of each fragment and will use coupling reagents such as carbodiimides (DIC). For racemized prone fragments, PyBop or HBTU/HOBt can be used. Amino acids with Bsmoc/tBu or Fmoc/tBu and Boc/Benzyl protection are equally suitable for use.

When Fmoc is used, the use of 4-(aminomethyl) piperidine or tris(2-aminoethyl)amine as the deblocking agent can avoid undesired side reactions. The resulting Fmoc adduct can be extracted with a phosphate aqueous buffer of pH 5.5 (Organic Process Research & Development 2003, 7, 2837). If Bsmoc is used, no buffer is required, only aqueous extractions are needed. Deprotections using these reagents occur in 30-60 minutes. Deblocking of the Fmoc group on the N-terminal residue provides a free terminal amine that is used for attachment of the tether moiety. In the compounds of the invention, tether moieties are attached through amide bonds to the N-terminal amine.

One advantage of solution phase synthesis is the ability to monitor the compound after every coupling step by mass spectrometry to see that the product is forming. In addition, a simple TLC system could be used to determine completion of reaction.

Attachment of Tethers

Tethers are attached to the terminal nitrogen of the N-terminal amino acid of the peptide chain using amide bond coupling:

The tether can be attached using solid phase procedures or in solution using an amide bond coupling. After the N-terminus is suitably coupled, the final compound is cleaved from the resin using an acidic cocktail (Peptide Synthesis and Applications, John Howl, Humana Press, 262p, 2005). Typically these cocktails use concentrated trifluoroacetic acid (80-95%) and various scavengers to trap carbocations and prevent side chain reactions. Typical scavengers include isopropylsilanes, thiols, phenols and water. The cocktail mixture is determined by the residues of the peptide. Special care needs to be taken with sensitive residues, such as methionine, aspartic acid, and cysteine. Typical deprotection occurs over 2-5 hours in the cocktail. A preferred deprotection cocktail include the use of triisopropylsilane (TIS), Phenol, thioanisole, dodecanethiol (DDT) and water. Methane sulfonic acid (MSA) may also be used in the cocktail (4.8%). A more preferred cocktail consists of (TFA:MSA:TIS:DDT:Water 82:4.5:4.5:4.5:4.5; 10 mL/0.1 mmol resin).

After deprotection, the resin is removed via filtration, and the final compound is isolated via precipitation from an organic solvent such as diethyl ether, m-tert-butyl ether, or ethyl acetate and the resulting solid collected via filtration or lyophilized to a powder. Purification of the peptide using reverse phase HPLC may be required to achieve sufficient purity. Generally, a gradient of aqueous solvent with an organic solvent will provide sufficient separation from impurities and deletion sequences. Typically 0.1% TFA is used as the aqueous and organic modifier, however, other modifiers such as ammonium acetate can also be used. After purification, the compound is collected, analyzed and fractions of sufficient purity are combined and lyophilized, providing the compound as a solid.

Amino Acid Reagents

The following commercially available orthogonally protected amino acids used can be used in the synthesis of compounds of the invention: Fmoc-Tyr(tBu)-OH, Fmoc-Ala-OH*H₂O, Fmoc-Arg(Pbf)-OH, Fmoc, Asn(Trt)-OH, Fmoc-Asp(tBu), Fmoc-Cys(tBu)-OH, Fmoc-Glu(tBu)-OH, Fmoc-Glx(Pbf)-OH, Fmoc-Gly-OH, Fmoc-His(Trt)-OH, Fmoc-Leu-OH, Fmoc-Ile-OH, Fmoc, Lys(tBu)-OH, Fmoc-Met-OH, Fmoc-Phe-OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Typ-OH, and Fmoc-Val-OH. Additional amino acids suitable for incorporation into the compounds of the invention (e.g., D amino acids, substituted amino acids and other protecting group variations) are also commercially available or synthesized by methods known in the art.

Analytical Methods

The compounds of the invention are analyzed for purity by HPLC using the methods listed below. Purification is achieved by preparative HPLC.

Fast LC/MS Method

Column: Phenomenex Luna C-5 20×30 mm

Flow: 1.0 ml/min

Solvent A: 0.1% TFA in Type I water

Solvent B: 0.1% TFA in Acetonitrile

UV 220 nm

Injection: 20 ul

Gradient 5-95% B (7 minutes); 95-5% B (1 minute); 5% B (4 minutes)

Analytical Purity Method

Column: Phenomenex Luna C-5 20×30 mm

Flow: 1.0 ml/min

Solvent A: 0.1% TFA in Type I water

Solvent B: 0.1% TFA in Acetonitrile

UV: 220 nm

Injection: 20 ul

Gradient: 2-95% B (10 minutes); 95-2% B (2 minutes); 2% B (2 minutes)

Preparative LC/MS Method

Column: Phenomenex Luna C-5 250×150 mm

Flow: 5.0 ml/min

Solvent A: 0.1% TFA in Type I water

Solvent B: 0.1% TFA in Acetonitrile

UV: 220 nm

Injection: 900 ul

Gradient: 35% B (5 minutes); 35-85% B (13 minutes); 85-35% B (0.5 minutes); 35% B (1.5 minutes)

The compounds listed in Tables 14-17 or pharmaceutically acceptable salts thereof were prepared according to the methods described herein.

TABLE 14 CXCR4 i1 loop compounds MS N-terminus MS Observed No.: Loop Sequence T-L C-terminus Theoretical Ion 1 i1 AGYQKKLRSMT C₁₅H₃₁C(O)— NH₂ D (SEQ ID NO.) 2 i1 MAYQKKLRSMT C₁₅H₃₁C(O)— NH₂ D (SEQ ID NO.) 3 i1 MGAQKKLRSMT C₁₅H₃₁C(O)— NH₂ D (SEQ ID NO.) 4 i1 MGYAKKLRSMT C₁₅H₃₁C(O)— NH₂ D (SEQ ID NO.) 5 i1 MGYQKKLRAM C₁₅H₃₁C(O)— NH₂ TD (SEQ ID NO.) 6 i1 MGYQKKLRSAT C₁₅H₃₁C(O)— NH₂ D (SEQ ID NO.) 7 i1 MGYQKKLRSM C₁₅H₃₁C(O)— NH₂ AD (SEQ ID NO.) 8 i1 MGYQKKLRSMT C₁₅H₃₁C(O)— NH₂ A (SEQ ID NO.) 9 i1 MGYQAKLRSMT C₁₅H₃₁C(O)— NH₂ D 10 i1 MGYQKKLASMT C₁₅H₃₁C(O)— NH₂ D 11 i1 MGYQKALRSMT C₁₅H₃₁C(O)— NH₂ D (SEQ ID NO.) 12 i1 MGYQKKARSM C₁₅H₃₁C(O)— NH₂ TD (SEQ ID NO.) 13 i1 mGYQKKLRSMT C₁₅H₃₁C(O)— NH₂ D (SEQ ID NO.) 14 i1 MGyQKKLRSMT C₁₅H₃₁C(O)— NH₂ D (SEQ ID NO.) 15 i1 MGYqKKLRSMT C₁₅H₃₁C(O)— NH₂ D (SEQ ID NO.) 16 i1 MGYQkKLRSMT C₁₅H₃₁C(O)— NH₂ D (SEQ ID NO.) 17 i1 MGYQKkLRSMT C₁₅H₃₁C(O)— NH₂ D (SEQ ID NO.) 18 i1 MGYQKKlRSMT C₁₅H₃₁C(O)— NH₂ D (SEQ ID NO.) 19 i1 MGYQKKLrSMT C₁₅H₃₁C(O)— NH₂ D (SEQ ID NO.) 20 i1 MGYQKKLRsMT C₁₅H₃₁C(O)— NH₂ D (SEQ ID NO.) 21 i1 MGYQKKLRSmT C₁₅H₃₁C(O)— NH₂ D (SEQ ID NO.) 22 i1 MGYQKKLRSMt C₁₅H₃₁C(O)— NH₂ D (SEQ ID NO.) 23 i1 MGYQKKLRSMT C₁₅H₃₁C(O)— NH₂ d (SEQ ID NO.) 24 i1 GSHYQKKLRSST C₁₅H₃₁C(O)— NH₂ D (SEQ ID NO.) 25 i1 SGYQKKLRSSTD C₁₇H₃₃C(O)— NH₂ (SEQ ID NO.) 26 i1 SGYQKKLRSSTD C₁₆H₃₁C(O)— NH₂ (SEQ ID NO.) 27 i1 sGYQKKLRSSTD C₁₅H₃₁C(O)— NH₂ (SEQ ID NO.) 28 i1 GSGYQKKLRSST C₁₅H₃₁C(O)— NH₂ D (SEQ ID NO.) 29 i1 YQKKLRSSTD C₁₅H₃₁C(O)— NH₂ (SEQ ID NO.) 30 i3 JGYQKKLRSJTD C₁₅H₃₁C(O)— NH₂ (SEQ ID NO.) 31 i3 JGYQKKLRSJTD C₁₅H₃₁C(O)- NH₂ (SEQ ID NO.) 32 i1 MGYQKKLRSMT CH₃C(O)— NH₂ D (SEQ ID NO.) 33 i1 MGYQKKLRSMT Footnote: 1 NH₂  655.8  655.5 D (SEQ ID NO.) 34 i1 LVMGYQKKLRS C₁₅H₃₁C(O)— NH₂  954.7, 636.8  954.2, 646.3 MTD (SEQ ID NO.) 35 i1 VMGYQKKLRS C₁₅H₃₁C(O)— NH₂  898.1  897.7 MTD (SEQ ID NO.) 36 i1 MGYQKKLRSMT C₁₅H₃₁C(O)— NH₂  912.7  912.2 DK (SEQ ID NO.) 37 i1 MGYQKKLRSMT C₁₅H₃₁C(O)— NH₂  994.3  993.7 DKY (SEQ ID NO.) 38 i1 MGYQKKLRSMT C₁₅H₃₁C(O)— NH₂  752.9  753 DKYRL (SEQ ID NO.) 39 i1 MGYQKKLRSMT C₁₅H₃₁C(O)— NH₂  836.4  836 DKYRLHL (SEQ ID NO.) 40 i1 YQKKLRSMTDK C₁₅H₃₁C(O)— NH₂ 1253.0, 835.7, 1254, 836, YRLHLSV (SEQ  627.2  627.50 ID NO.) 41 i1 KKLRSMTDKYR C₁₅H₃₁C(O)— NH₂ 1107.4, 738.6, 1107.0, 738.0, LHLSV (SEQ ID  554.2  554 NO.) 42 i1 KKLRSMTDKYR C₁₅H₃₁C(O)— NH₂ 1014.3, 676.5 1014.0, 676.0 LHL (SEQ ID NO.) 43 i1 KKLRSMTDKYR C₁₅H₃₁C(O)— NH₂  957.7, 638.8  958.0, 638.0 LH (SEQ ID NO. (SEQ ID NO. 42)) 44 i1 KKLRSMTDKYR C₁₅H₃₁C(O)— NH₂  889.2, 592.1  888.0, 592.0 L (SEQ ID NO.) 45 i1 KKLRSMTDKYR C₁₅H₃₁C(O)— NH₂  832.6  833 (SEQ ID NO.) 46 i1 KKLRSMTDKY C₁₅H₃₁C(O)— NH₂  754.5  754 (SEQ ID NO.) 47 i1 MGYQKKLRSMT C₁₅H₃₁C(O)— NH₂  827.8, 621.0  828.0, 621.0 DKYRI (SEQ ID NO.) 48 i1 MGYQKKLRSMT Footnote: 2 NH₂  837.4  837.4 DKYRI (SEQ ID NO.) 49 i1 MGYQKKLRSMT C₁₅H₃₁C(O)— NH₂  752.9  753 DKYRI (SEQ ID NO.) 50 i1 SGYQKKLRSSTD Footnote: 2 NH₂  931.2  931 (SEQ ID NO.) 51 i1 MGYQKKLRSMT Footnote: 2 NH₂  975.3, 650.5  975.0, 650.5 D (SEQ ID NO.) 52 i1 QKKLRSMTDKY CH₃C(O)— NHC₁₆H₃₃  645.2  645 RI (SEQ ID NO.) 53 i1 MGYQKKLRSMT C₁₅H₃₁C(O)— NH₂  683.7  684 DKYRLHL (SEQ ID NO.) 54 i1 MGYQKKLRSMT Footnote: 2 NH₂  920.9, 690.9  921.0, 691.0 DKYRLHL (SEQ ID NO.) 55 i1 MGYQKKLRSMT C₁₅H₃₁C(O)— NH₂  898.4  898 DKYRLHLSV (SEQ ID NO.) 56 i1 MGYQKKLRSMT Footnote: 2 NH₂  982.9, 737.5  982.0, 737.0 DKYRLHLSV (SEQ ID NO.) 58 i1 MGYQKKLRSMT CH₃C(O)— NH₂  814.5  814.5 DK (SEQ ID NO.) 59 i1 MGYQKKLRSMT CH₃C(O)— NHC₁₆H₃₃  926.7, 618.1  926.5, 618 DK (SEQ ID NO.) 60 i1 MGYQKKLRSMT Footnote: 2 NH₂  693.2  693.2 DK (SEQ ID NO.) 61 i1 KKLCRSMTDKC C₁₅H₃₁C(O)— NH₂  991.2  990 YRL (SEQ ID NO.) 62 i1 KKLRCSMTDCK C₁₅H₃₁C(O)— NH₂ YRL (SEQ ID NO.) 63 i1 KKLRSMTDKYR C₁₅H₃₁C(O)— NH₂  902.2  901.7 L (SEQ ID NO.) 64 i1 KKLRSMTDKYR C₁₅H₃₁C(O)— NH₂  911.2  910.5 L (SEQ ID NO.) 65 i1 KRMKTSLYDGR C₁₅H₃₁C(O)— NH₂  752.9  752.3 MQYLK (SEQ ID NO.) 66 i1 YTKRLDSHRKL C₁₅H₃₁C(O)— NH₂  957.7  956.7 KM (SEQ ID NO.) 67 i1 MGYQKKLRSMT CH3C(O)— NH₂  687.8  687 DKYRL (SEQ ID NO.) 68 i1 KKLRSXTDKYR C₁₅H₃₁C(O)— NH₂  632.8  632.3 LH (SEQ ID NO.) 69 i1 SGYQKKLRSSTD C₁₅H₃₁C(O)— NH₂ (SEQ ID NO.) 70 i1 SGYQKKLRSSTD C₁₆H₃₃O₂C(O)— NH₂ (SEQ ID NO.) 71 i1 SGYQKKLRSSTD C₂₃H₃₉OC(O)— NH₂ (SEQ ID NO.) 72 i1 MGYQKKLRSST C₁₅H₃₁C(O)— NH₂ D (SEQ ID NO.) 73 i1 SGYQKKLRSMT C₁₅H₃₁C(O)— NH₂ D(SEQ ID NO.) 117 i1 kKLRSMTDKYR Pal LH (SEQ ID NO. 89) 118 i1 KkLRSMTDKYR Pal LH (SEQ ID NO. 90) 119 i1 KKlRSMTDKYRL Pal H (SEQ ID NO: 91) 120 i1 KKLrSMTDKYRL Pal H (SEQ ID NO. 92) 121 i1 KKLRsMTDKYR Pal LH (SEQ ID NO. 93) 122 i1 KKLRSmTDKYR Pal LH (SEQ ID NO. 94) 123 i1 AKLRSMTDKYR Pal LH (SEQ ID NO. 95) 124 i1 KALRSMTDKYR Pal LH (SEQ ID NO. 96) 125 i1 KKARSMTDKYR Pal LH (SEQ ID NO. 97) 126 i1 KKLASMTDKYR Pal LH (SEQ ID NO. 98) 127 i1 KKLRAMTDKYR Pal LH (SEQ ID NO. 99) 128 i1 KKLRSATDKYR Pal LH (SEQ ID NO. 100) 129 i1 AGYQKKLRSMT Pal DKYRL (SEQ ID NO. 101) 130 i1 MAYQKKLRSMT Pal DKYRL (SEQ ID NO. 102) 131 i1 MGAQKKLRSMT Pal DKYRL (SEQ ID NO. 103) 132 i1 MGYAKKLRSMT Pal DKYRL (SEQ ID NO. 104) 133 i1 MGYQAKLRSMT Pal DKYRL (SEQ ID NO. 105) 134 i1 MGYQKALRSMT Pal DKYRL (SEQ ID NO. 106) 135 i1 MGYQKKARSM Pal TDKYRL (SEQ ID NO. 107) 136 i1 MGYQKKLASMT Pal DKYRL (SEQ ID NO. 108) 137 i1 KKLRSMTDKYR Myr LH (SEQ ID NO. 42) 138 i1 KKLRSMTDKYR Lca LH (SEQ ID NO. 42) 139 i1 KKLRSMADKYR Pal LH (SEQ ID NO.) 140 i1 KKLRSMTAKYR Pal LH (SEQ ID NO.) 141 i1 KKLRSMTDAYR Pal LH (SEQ ID NO.) 142 i1 KKLRSMTDKAR Pal LH (SEQ ID NO.) 143 i1 KKLRSMTDKYA Pal LH (SEQ ID NO.) 144 i1 KKLRSMTDKYR Pal AH (SEQ ID NO.) 145 i1 KKLRSMTDKYR Pal LA (SEQ ID NO.) 146 i1 MGYQKKLRAM Pal TDKYRL (SEQ ID NO.) 147 i1 MGYQKKLRSAT Pal DKYRL (SEQ ID NO.) 148 i1 MGYQKKLRSM Pal ADKYRL (SEQ ID NO.) 149 i1 MGYQKKLRSMT Pal AKYRL (SEQ ID NO.) 150 i1 MGYQKKLRSMT Pal DAYRL (SEQ ID NO.) 151 i1 MGYQKKLRSMT Pal DKARL (SEQ ID NO.) 152 i1 MGYQKKLRSMT Pal DKYAL (SEQ ID NO.) 153 i1 MGYQKKLRSMT Pal DKYRA (SEQ ID NO.) 154 i1 KKLRSMtDKYRL Pal H (SEQ ID NO.) 155 i1 KKLRSMTdKYR Pal LH (SEQ ID NO.) 156 i1 KKLRSMTDKYrL Pal H (SEQ ID NO.) 157 i1 KKLRSMTDKYRl Pal H (SEQ ID NO.) 158 i1 KKLRSMTDKYR Pal Lh (SEQ ID NO.) 159 i1 MGYQKKLRSMT Pal DKYRl (SEQ ID NO.) 160 i1 MGYQKKLRSMT Pal DKYrL (SEQ ID NO.) 161 i1 MGYQKKLRSMT Pal DKyRL (SEQ ID NO.) 162 i1 MGYQKKLRSMT Pal DkYRL (SEQ ID NO.) 163 i1 MGYQKKLRSMT Pal dKYRL (SEQ ID NO.) 164 i1 MGYQKKLRSMt Pal DKYRL (SEQ ID NO.) 165 i1 mGYQKKLRSMT Pal DKYRL (SEQ ID NO.) 166 i1 MGyQKKLRSMT Pal DKYRL (SEQ ID NO.) 167 MGYqKKLRSMT Pal DKYRL (SEQ ID NO.) 168 i1 MGYQkKLRSMT Pal DKYRL (SEQ ID NO.) 169 i1 MGYQKkLRSMT Pal DKYRL (SEQ ID NO.) 170 i1 MGYQKKlRSMT Pal DKYRL (SEQ ID NO.) 171 i1 MGYQKKLrSMT Pal DKYRL (SEQ ID NO.) 172 MGYQKKLRsMT Pal DKYRL (SEQ ID NO.) 173 i1 MGYQKKLRSmT Pal DKYRL (SEQ ID NO.) 174 i1 KKLRSMTDKYRl Pal S (SEQ ID NO.) 175 i1 MGYQKKLRSMT Pal DKYRL (SEQ ID NO.) 176 i1 MGYQKKLRSMT Elaidic DKYRL (SEQ ID NO.) 177 i1 MGYQKKLRSMT Oleic DKYRL (SEQ ID NO.) 178 i1 MGYQKKLRSMT 3- DKYRL (SEQ ID (dodecyloxy) NO.) propanoate 179 i1 MGYQKKLRSMT DKYRL (SEQ ID NO. ) 180 i1 KKLRSMTDKYR Pal LH (SEQ ID NO.) 181 i1 KKLRSMTDKYR 3- LH (SEQ ID NO.) (dodecyloxy) propanoate 182 i1 KKLRSMTDKYR LH (SEQ ID NO.) 183 i1 KKLRSMTDKYR LH (SEQ ID NO.) 184 i1 KKLRSMTDKYR LH (SEQ ID NO.) 185 i1 KKLRSMTDKYR LH (SEQ ID NO.) 186 i1 MGYQKKLRSMT DKYRL (SEQ ID NO.) 187 i1 MGYQKKLRSMT DKYRL (SEQ ID NO.) 188 i3 MGYQKKLRSMT DKYRL (SEQ ID NO.) 189 i1 MGYQKKLRSpT Pal DKYRL (SEQ ID NO.) 190 i1 MGYQKKLRpMT Pal DKYRL (SEQ ID NO.) 191 i1 MGYQKKLpSMT Pal DKYRL (SEQ ID NO.) 192 i1 MGYQKKpRSMT Pal DKYRL (SEQ ID NO.) 193 i1 MGYQKKLRSMP Pal DKYRL (SEQ ID NO.)

TABLE 15 CXCR4 i2 loop compounds N- MS Sample terminus C- MS Observed Lot Loop T-L Sequence terminus Theoretical Ion 74 i2 C₁₅H₃₁C(O)— DRYLAIVHATNSQR —(NH)C16H33 679.4, 905.5 679.3, 905.0 PRKLL (SEQ ID NO.) 75 i2 C₁₅H₃₁C(O)— VHATNSQRPRKLLA NH₂ 612.8 613.0 EKVVY (SEQ ID NO.) 76 i2 C₃₁H₆₂NC(O)— DRYLAIVHATNSQR NH₂ 686.6 686.6 PRKLL (SEQ ID NO.) 77 i2 C₁₅H₃₁C(O)— DRYLAIVHATNSQR NH₂ 623.3 623.5 PRKLL (SEQ ID NO.) 78 i2 C₁₅H₃₁C(O)— VHATNSQRPRKLLA NH₂ 915.2 915 (SEQ ID NO.) 79 i2 C₁₅H₃₁C(O)— HATNSQRPRKL NH₂ 773.5 773.9 (SEQ ID NO.) 80 i2 C₁₅H₃₁C(O)— HATNSQRPRKLLA NH₂ 865.6 865.5 (SEQ ID NO.) 81 i2 C₁₅H₃₁C(O)— HATNSQRPRKLLAE NH₂ 930.2 930.5 (SEQ ID NO.) 82 i2 C₁₅H₃₁C(O)— HATNSQRPRKLLAE NH₂ 663.1 663.0 (SEQ D NO.) K 83 i2 C₁₅H₃₁C(O)— HATNSQRPRKLLAE NH₂ 696.2 696.0 KV (SEQ ID NO.)

TABLE 16 CXCR4 i3 loop compounds C- N- MS MS Sequence terminus terminus MW Theoretical Observed Ion 84 HSKKGHQKR NH₂ C₁₅H₃₁C(O)— 1783.258 KALK (SEQ ID NO.) 85 HSKGHQKR NH₂ C₁₅H₃₁C(O)— 1655.086 KALK (SEQ ID NO. 369) 87 HSKGHQKRK NH₂ C27H50N3 1924.449 963.2 962.0 QALK O2SC(O)— (SEQ ID NO.) 88 SKLSHSKGHQ NH₂ C₁₅H₃₁C(O)— 2598.225 867.1, 866.7, 650.0  KRKALKTTVIL 650.6 (SEQ ID NO.) 89 KLSHSKGHQ NH₂ C₁₅H₃₁C(O)— 2511.147 838.0, 837.5, 1255.8 KRKALKTTVIL 1256.6 (SEQ ID NO.) 90 KLSHSKGHQ NH₂ C₁₅H₃₁C(O)— 2284.832 762.6 762.0 KRKALKTTV (SEQ ID NO.) 91 KLSHSKGHQ NH₂ C₁₅H₃₁C(O)— 2084.597 1043.3 1043.0 KRKALKT (SEQ ID NO.) 92 KLSHSKGHQ NH₂ C₁₅H₃₁C(O)— 1983.493 992.7 992.0 KRKALK (SEQ ID NO.) 93 KLSHSKGHQ NH₂ C₁₅H₃₁C(O)— 1855.321 619.4, 619.3, 929.0  KRKAL (SEQ 928.7 ID NO.) 94 KLSHSKGHQ NH₂ C₁₅H₃₁C(O)— 1742.163 581.7, 582.0, 872.0  KRKA (SEQ 872.1 ID NO.) 95 LSHSKGHQK NH₂ C₁₅H₃₁C(O)— 1855.321 928.7 928.0 RKALK (SEQ ID NO.) 96 SHSKGHQKR NH₂ C₁₅H₃₁C(O)— 1742.163 581.7 585.0 KALK (SEQ ID NO.) 97 HSKGHQKRK NH₂ C₁₅H₃₁C(O)— 1756.19 879.1 879.0 ALKT (SEQ ID NO.) 98 HSKGHQKRK NH₂ C₁₅H₃₁C(O)— 1857.294 620.1 619.9 ALKTT (SEQ ID NO.) 99 HSKGHQKRK NH₂ C₁₅H₃₁C(O)— 1956.425 653.0 653.0 ALKTTV (SEQ ID NO.) 100 HSKGHQKRK NH₂ C₁₅H₃₁C(O)— 2069.583 733.0 733.6 ALKTTVI (SEQ ID NO.) 101 SKLSHSKGHQ NH₂ C₁₅H₃₁C(O)— 2070.571 1036.3 1036.0 KRKALK (SEQ ID NO.) 102 IIISKLSHSKG NH₂ C₁₅H₃₁C(O)— 2511.147 628.8 628.7 HQKRKALKT (SEQ ID NO.) 103 IIISKLSHSKG NH₂ C₃₁H₆₂NC(O)— 2765.556 692.4 692.4 HQKRKALKT (SEQ ID NO.) 104 IIISKLSHSKG —(NH)C16H33 C₁₅H₃₁C(O)— 2735.573 684.9 684.7 HQKRKALKT 105 KLSHSKGHQ NH₂ C₃₁H₆₂NC(O)— 2764.571 684.9 685.0 KRKALKTTVIL (SEQ ID NO.) 106 QHLHIALKKS NH₂ C₁₅H₃₁C(O)— 2598.225 650.6 650.0 TSRKVKSGTLK (SEQ ID NO.) Foot Note 1 of Tables is

Footnote 2 of the tables is:

TABLE 17 CXCR4 i4 loop compounds MS C- MS Observed No. Loop N-terminus MW terminus Sequence Theoretical Ion 107 i4 C₃₁H₆₂NC(O)— 4248.067 NH₂ GAKFKTSAQHALTS 1063.0 1063.0 VSRGSSLKILSKGKR GGHSSVST (SEQ ID NO.) 108 i4 C₃₁H₆₂NC(O)— 3592.41 NH₂ GAKFKTSAQHALTS 1198.5 1199 VSRGSSLKILSKGKR G (SEQ ID NO.) 109 i4 C₁₅H₃₁C(O)— 3994.644 NH₂ GAKFKTSAQHALTS  999.7, 799.2  800.0, VSRGSSLKILSKGKR 1000.0 GGHSSVST (SEQ ID NO.) 110 i4 C₁₅H₃₁C(O)— 3870.571 NH₂ GAKFKTSAQHALTS  775.1  774.7 VSRGSSLKILSKGKR GGSCFH (SEQ ID NO.) 111 i4 C₁₅H₃₁C(O)— 3338.987 NH₂ GAKFKTSAQHALTS  835.8, 1114.0 1835.8, VSRGSSLKILSKGKR 1114.0 G (SEQ ID NO.) 112 i4 C₁₅H₃₁C(O)— 3052.8 NH₂ GAKFKTSAQHALTS  764.2  764.6 VSRGSSLKILSGGK 1018.6 1019.0 (SEQ ID NO.) 113 i4 C₁₅H₃₁C(O)— 2083.477 NH₂ GAKFKTSAQHALTS  695.5, 1042.8  695.0, VSRG (SEQ ID NO.) 1042.0 114 i4 C₁₅H₃₁C(O)— 2940.526 NH₂ GAKFKTSAQHALTS  736.1, 981.2  736.0, 982.0 VSRGSSLKILSK (SEQ ID NO.) 115 i4 C₁₅H₃₁C(O)— 2498.961 NH₂ GAKFKTSAQHALTS  625.8, 834.0  626.0, 834.0 VSRGSSLK (SEQ ID NO.) 116 i4 C₁₅H₃₁C(O)— 1938.18 NH₂ GAKFKTSAQHALTS  646.7  647.3 VR (SEQ ID NO.)

Synthesis of Selected Compounds

(SEQ. ID No. 253) Compound No. 88 (Pal-SKLSHSKGHQKRKALKTTVIL-amide)

Compound 88 was synthesized as described above on Rink amide resin at 0.1 mmol scale. Amino acids were coupled sequentially as described above. Following deprotection of the Fmoc group on the N-terminal residue serine, the N-terminal amine was capped with palmitic acid (10 eq.), HBTU (10 eq.) and DIEA (10 eq.) as described above. The compound was cleaved from the resin by TFA containing MS, TIS, DDT, and water (82: 4.5:4.5:4.5:4.5; 10 mL), filtered through a coarse frit Buchner full, triturated with ether and the resulting precipitate collected by centrifugation. Crude peptide was taken up in minimum amount of DMSO and TFA and purified by RP-HPLC as described previously. Fractions with correct MW were pooled and lyophilized and analyzed for purity using Method A. The yield of representative lots is illustrated in the following table.

Lot # Yield (mg) 1 4 2 2.7 3 6.9

Compound No. 90 (Pal-KLSHSKGHQKRKALKTTV-amide)

Compound 90 was synthesized as described for Compound 88. The yield of representative lots is illustrated in the following table.

Lot # Yield (mg) 1 8.6

Compound No. 38 (Pal-MGYQKKLRSMTDKYRL-amide)

Compound No. 38 was synthesized as described for Compound 88. The yield of representative lots is illustrated in the following table.

Lot # Yield (mg) 1 1.8 2 3.4 3 11.0

Compound No. 44 (Pal-KKLRSMTDKYRL-amide)

Compound No. 44 was synthesized as described for Compound No. 88. The yield of representative lots is illustrated in the following table.

Lot # Yield (mg) 1 7.9 2 7.3 3 9.7

Methods of Screening Functional Assays

Functional assays suitable for use in detecting and characterizing GPCR signaling include Gene Reporter Assays and Calcium Flux assays, cAMP and kinase activation assays. Several suitable assays are described in detail below.

Gene Reporter Assays

Cells expressing the GPCR of interest can be transiently or stably transfected with a reporter gene plasmid construct containing an enhancer element which responds to activation of a second messenger signaling pathway or pathways, thereby controlling transcription of a cDNA encoding a detectable reporter protein. GPCR expression can be the result of endogenous expression on a cell line or cell type or the result of stable or transient transfection of DNA encoding the receptor of interest into a cell line by means commonly used in the art. Immortalized cell lines or primary cell cultures can be used.

If the activated pathway is stimulatory (e.g., Gs or Gq), agonist activity results in activation of transcription factors, in turn causing an increase in reporter gene transcription, detectable by an increase in reporter activity. To test for agonist or inverse agonist activity, cells expressing the GPCR and the reporter gene construct can be challenged by the test compound for a predetermined period of time (e.g., 2-12 hours, typically 4 hours). Cells can then be assessed for levels of reporter gene product. Inverse agonists will suppress levels of reporter to below basal levels in a dose dependent manner. To test for antagonist or inhibitory activity through a stimulatory pathway, cells expressing both the GPCR and the reporter gene construct can be activated by a receptor agonist to increase gene reporter product levels. Treatment with antagonists will counter the effect of agonist stimulation in a dose- and receptor-dependent manner.

To test for agonist activity on receptor signaling through an inhibitory pathway (e.g., Gi, which couples to CXCR4), cells can be treated with a systematic activator (e.g., forskolin) to increase levels of reporter gene product. Activation of Gi by treatment with receptor agonist will inhibit this expression by inhibiting adenylyl cyclase. To screen for antagonist activity, test compounds can be assessed for the ability to counter agonist inhibition of adenylyl cyclase, resulting in increase reporter transcription.

Alternatively, a plasmid construct expressing the promiscuous G-protein Gal6 can be used to obtain a positive signal from a GPCR which normally couples to an inhibitory G-protein. Co-expression of the chimeric G-protein Gaq/Gai5 (Coward et al. Analytical Biochemistry 270, 242-248 (1999)) allows coupling to Gi-coupled receptors and conversion of second messenger signaling from the inhibitory Gi pathway to the stimulatory Gq pathway. Agonist and antagonist assessment in these systems is the same as the stimulatory pathways. Well-to-well variation caused by such factors as transfection efficiency, unequal plating of cells, and cell survival rates can be normalized in transient transfection assays by co-transfecting a constitutively expressing reporter gene with a non-interfering signal independent of the regulated reporter.

Chemotaxis Assay

Chemotaxis assays were utilized to determine the effect of compound on the directed migration of cells in response to chemokine. Cells that express a receptor of interest were placed in the upper chamber of a Transwell chemotaxis plate

(Corning) and allowed to migrate through a polycarbonate membrane to a lower chamber containing the appropriate receptor-specific ligand. To test for antagonist or potentiating activity, cells were mixed with the desired concentration of compound prior to addition to the upper chamber. Conversely, agonist activity was determined by adding compound in the bottom chamber only without endogenous chemokine. The effect of compound is quantified by several parameters, including the extent of maximum response, the shift of agonist dose-response curves, and the area under the curve.

To measure the CXCR4-dependent migration of cells, the appropriate concentration of CXCL12 (SDF1a) or test compound was diluted in phenol red-free RMPI-1640/20 mM HEPES/0.5% BSA buffer and placed in the bottom chamber of a transwell apparatus. CCRF-CEM cells, a human T-cell ALL line that endogenously expresses CXCR4, were washed twice in buffer and resuspended at 133,000 cells/ml. A 75 μl sample of this suspension is mixed with the test compound of interest and placed in the upper chamber of a 5-micron transwell apparatus.

To initiate cell migration, the assembled transwell plate was placed in a 37° C., 0.5% CO₂ incubator for a specified time interval, typically between 30 and 120 minutes. After incubation, the unit was disassembled and the lower chamber placed at −80° C. overnight to facilitate lysis of cells. To quantify migrated cells, plates were thawed at 37° C. in a humidified chamber, and then a sample volume was removed from each well and mixed with an equal volume of CyQuant (Invitrogen) working solution in opaque plates. The fluorescence intensity of each well represents the DNA content and is directly proportional to cell number. Each sample was typically run in duplicate or triplicate and each plate included two separate negative controls. The plate background control, which included no cells in the upper chamber, was subtracted from all values. The negative control had no agonist added in the lower chamber, and served to establish the baseline for random migration. A similar procedure was followed for chemotaxis using SUP B-15 cells.

Calcium Flux Assay

Calcium Flux Assay is one of the most popular cell-based GPCR functional assays. It most often uses calcium sensing fluorescent dyes such as fura2 AM, fluo-4 and Calcium-4 to measure changes in intracellular calcium concentration. It is used mainly to detect GPCR signaling via Gaq subunit. Activation of these Gq-coupled GPCRs leads to activation of phospholipase C, which subsequently leads to increase in inositol phosphate production. IP3 receptors on endoplasmic reticulum sense the change then release calcium into cytoplasm. Intracellular calcium binding to the fluorescent dyes can be detected by instruments that quantify fluorescent intensities, such as FLIPR Tetra, Flexstation (MDS) and FDSS (Hamamatsu). In additional to assess Gq-couple receptor signaling, calcium flux assay can also be used to study Gs and Gi couple receptors by co-expressing CNG (cyclic nucleotide gated calcium channel) or chimeric G-proteins (Gqi5, Gsi5 for example). Activation of some Gi-coupled receptors can also be detected by calcium flux assay via Gβγmediated phospholipase C activation.

CXCR4 Testing

The calcium flux assay was used to assess SDF-1α activation of CXCR4 in CCRF-CEM cells (human T lymphoblasts from acute lymphoblastic leukemia). CCRF-CEM cells were seeded into 96-well black plates with clear bottom at 200K/well in RPMI 1640 media with 20 mM HEPES containing 0.2% BSA. After dye loading by incubating with Calcium-4 dye at 37° C. for 1 hour, cell plates were read at 37° C. using the Flexstation 3 workstation. The addition of test compounds or reference antagonists was accomplished either by manual pipetting or by liquid handling using the Flexstation. The latter allows the assessment of intrinsic agonist activity of the test compounds by measuring initial changes in fluorescent intensity.

After incubation of 24 minutes at 37° C., SDF-1α was added and receptor activation was assessed by measuring changes in fluorescent intensity using the Flexstation.

Representative Results

CXCR4 i1 loop compound Calcium Flux Data N- C- Comp. # Loop terminus Sequence terminus MW IC50 (nM)  38 i1 Pal MGYQKKLRSMTD Amide 2255.831 98 KYRL (SEQ ID NO.) 129 i1 Pal AGYQKKLRSMTD Amide 2195.712 197 KYRL (SEQ ID NO.) 130 i1 Pal MAYQKKLRSMTD Amide 2269.857 125 KYRL (SEQ ID NO.) 131 i1 Pal MGAQKKLRSMTD Amide 2163.735 147 KYRL (SEQ ID NO.) 132 i1 Pal MGYAKKLRSMTD Amide 2198.779 213 KYRL (SEQ ID NO.) 133 i1 Pal MGYQAKLRSMTD Amide 2198.736 200 KYRL (SEQ ID NO.) 134 i1 Pal MGYQKALRSMTD Amide 2198.736 250 KYRL (SEQ ID NO.) 135 i1 Pal MGYQKKLRSMTD Amide 2213.751 175 KYRL (SEQ ID NO.) 136 i1 Pal MGYQKKLRSMTD Amide 2170.723 302 KYRL (SEQ ID NO.) 146 i1 Pal MGYQKKLRAMTD Amide 2239.831 170 KYRL (SEQ ID NO.) 147 i1 Pal MGYQKKLRSATD Amide 2195.712 54 KYRL (SEQ ID NO.) 148 i1 Pal MGYQKKLRSMAD Amide 2225.805 298 KYRL (SEQ ID NO.) 149 i1 Pal MGYQKKLRSMTA Amide 2211.821 126 KYRL (SEQ ID NO.) 150 i1 Pal MGYQKKLRSMTD Amide 2198.736 313 AYRL (SEQ ID NO.) 151 i1 Pal MGYQKKLRSMTD Amide 2163.735 >10000 KARL (SEQ ID NO.) 152 i1 Pal MGYQKKLRSMTD Amide 2170.723 >10000 KYAL (SEQ ID NO.) 153 i1 Pal MGYQKKLRSMTD Amide 2213.751 >10000 KYRA (SEQ ID NO.) 159 i1 Pal MGYQKKLRSMTD Amide 2255.831 >10000 KYRL (SEQ ID NO.) 160 i1 Pal MGYQKKLRSMTD Amide 2255.831 5731 KYrL (SEQ ID NO.) 161 i1 Pal MGYQKKLRSMTD Amide 2255.831 >10000 KyRL (SEQ ID NO.) 162 i1 Pal MGYQKKLRSMTDk Amide 2255.831 291 YRL (SEQ ID NO.) 163 i1 Pal MGYQKKLRSMTdK Amide 2255.831 623 YRL (SEQ ID NO.) 164 i1 Pal MGYQKKLRSMtDK Amide 2255.831 322 YRL (SEQ ID NO.) 165 i1 Pal mGYQKKLRSMTD Amide 2255.831 112 KYRL (SEQ ID NO.) 166 i1 Pal MGyQKKLRSMTDK Amide 2255.831 129 YRL (SEQ ID NO.) 167 i1 Pal MGYqKKLRSMTDK Amide 2255.831 116 YRL (SEQ ID NO.) 168 i1 Pal MGYQkKLRSMTDK Amide 2255.831 119 YRL (SEQ ID NO.) 169 i1 Pal MGYQKkLRSMTDK Amide 2255.831 88 YRL (SEQ ID NO.) 170 i1 Pal MGYQKKlRSMTDK Amide 2255.831 72 YRL (SEQ ID NO.) 171 i1 Pal MGYQKKLrSMTDK Amide 2255.831 72 YRL (SEQ ID NO.) 172 i1 Pal MGYQKKLRsMTD Amide 2255.831 90 KYRL (SEQ ID NO.) 173 i1 Pal MGYQKKLRSmTD Amide 2255.831 97 KYRL (SEQ ID NO.)

Results

Representative results from the following tables are provided in FIGS. 1-4.

TABLE 18 CXCR4 i1 loop CHTX data CEM and Sup-B-15 cells Peak Test Peak Drug Cell AUC Max (% Comp. Control Peak Comp. # Sequence Conc Type (% of) of) (nM) (nM) Ratio 33 MGYQKKLRSM  1.0 uM CEM 68.9 68.09 1 1 1 TD (SEQ ID NO.) 33 MGYQKKLRSM  1.0 uM CEM 54.81 76.06 0.2 0.2 1 TD (SEQ ID NO.) 35 VMGYQKKLRS  1.0 uM SUP 31.7 49.27 1 5 0.2 MTD (SEQ ID B-15 NO.) 35 VMGYQKKLRS  1.0 uM CEM 57.9 56.97 5 5 1 MTD (SEQ ID NO.) 36 MGYQKKLRSM  1.0 uM SUP 49.94 54.8 1 5 0.2 TDK (SEQ ID NO.) B15 36 MGYQKKLRSM  1.0 uM CEM 101.76 119.07 0.2 1 0.2 TDK (SEQ ID NO.) 37 MGYQKKLRSM  1.0 uM SUP 63.52 91.09 1 5 0.2 TDKY (SEQ ID B-15 NO.) 37 MGYQKKLRSM  1.0 uM CEM 92.31 97.85 1 25 0.04 TDKY (SEQ ID NO.) 38 MGYQKKLRSM  1.0 uM SUP 32.38 49.56 1 5 0.2 TDKYRL (SEQ B-15 ID NO.) 38 MGYQKKLRSM  1.0 uM CEM 75.53 106.96 5 25 0.2 TDKYRL (SEQ ID NO.) 38 MGYQKKLRSM  1.0 uM CEM 46.27 71.48 0.2 1 0.2 TDKYRL (SEQ ID NO.) 39 MGYQKKLRSM  1.0 uM SUP 47.43 37.65 5 25 0.2 TDKYRLHL B-15 (SEQ ID NO.) 39 MGYQKKLRSM  1.0 uM CEM 37.55 59.71 1 25 0.04 TDKYRLHL (SEQ ID NO.) 40 YQKKLRSMTDK  1.0 uM SUP 71.92 71.22 5 25 0.2 YRLHLSV (SEQ B-15 ID NO.) 41 KKLRSMTDKYR  1.0 uM SUP 51.69 41.71 1 25 0.04 LHLSV (SEQ ID B-15 NO.) 41 KKLRSMTDKYR  1.0 uM CEM 66.71 76.8 0.2 25 0.01 LHLSV (SEQ ID NO.) 42 KKLRSMTDKYRYR  1.0 uM SUP 43.82 33.47 5 25 0.2 LHL (SEQ ID NO.) B-15 46 KKLRSMTDKYR  1.0 uM CEM 69.74 115.97 0.2 25 0.01 LHL (SEQ ID NO.) 43 KKLRSMTDKYR  1.0 uM SUP 70.8 55.84 1 25 0.04 LH (SEQ ID NO.) B-15 43 KKLRSMTDKYR  1.0 uM CEM 32.08 77.15 0.2 1 0.2 LH (SEQ ID NO.) 43 KKLRSMTDKYR  3.0 uM CEM 79.43 76.32 0.2 0.2 0.2 LH (SEQ ID NO.) 43 KKLRSMTDKYR  1.0 uM CEM 84.82 66.81 0 0 0.04 LH (SEQ ID NO.) 43 KKLRSMTDKYR  0.3 uM CEM 92.91 80.68 0 0 0.04 LH (SEQ ID NO.) 43 KKLRSMTDKYR  0.1 uM CEM 113.68 96.86 0.2 0.2 0.2 LH (SEQ ID NO.) 43 KKLRSMTDKYR 0.03 uM CEM 101.82 91.16 0.8 0.8 1 LH (SEQ ID NO.) 43 KKLRSMTDKYR 0.01 uM CEM 98.09 93.17 0.8 0.8 1 LH (SEQ ID NO.) 43 KKLRSMTDKYR  3.0 uM CEM 79.17 72.73 0 0.2 0.2 LH (SEQ ID NO.) 43 KKLRSMTDKYR  1.0 uM CEM 85.24 78.94 0 0 0.04 LH (SEQ ID NO.) 43 KKLRSMTDKYR  0.3 uM CEM 97.93 84.51 0 0 0.04 LH (SEQ ID NO.) 43 KKLRSMTDKYR  0.1 uM CEM 108.05 93.58 0 0.2 0.2 LH (SEQ ID NO.) 43 KKLRSMTDKYR 0.03 uM CEM 109.76 92.65 0.8 0.8 1 LH (SEQ ID NO.) 43 KKLRSMTDKYR 0.01 uM CEM 109.93 114.2 0.8 0.8 1 LH (SEQ ID NO.) 44 KKLRSMTDKYR  1.0 uM SUP 25.94 31.52 1 5 0.2 L (SEQ ID NO.) B-15 44 KKLRSMTDKYR  1.0 uM CEM 15.86 54.8 0.2 1 0.2 L (SEQ ID NO.) 44 KKLRSMTDKYR  1.0 uM CEM 92.31 97.85 1 25 0.04 L (SEQ ID NO.) 45 KKLRSMTDKYR  1.0 uM SUP 178.4 193.55 5 5 1 (SEQ ID NO.) B-15 46 KKLRSMTDKY  1.0 uM SUP 87.24 82.87 1 5 0.2 (SEQ ID NO.) B-15 48 MGYQKKLRSM  1.0 uM CEM 53.03 53.48 25 5 5 TDKYRI (SEQ ID NO.) 49 MGYQKKLRSM  1.0 uM CEM 50.9 62.66 1 5 0.2 TDKYRI (SEQ ID NO.) 50 SGYQKKLRSST  1.0 uM CEM 102.07 121.17 0.2 1 0.2 D (SEQ ID NO.) 50 SGYQKKLRSST  1.0 uM CEM 52.16 59.19 1 0.2 5 D (SEQ ID NO.) 52 QKKLRSMTDKY  1.0 uM CEM 111.49 97.78 1 5 0.2 RI (SEQ ID NO.) 52 QKKLRSMTDKY  1.0 uM CEM 76.62 92.8 0.2 1 0.2 RI (SEQ ID NO.) 52 QKKLRSMTDKY  1.0 uM CEM 45.5 63.35 0.2 0.2 1 RI (SEQ ID NO.) 53 MGYQKKLRSM  1.0 uM CEM 60.98 68.45 1 0.2 5 TDKYRLHL (SEQ ID NO.) 53 MGYQKKLRSM  1.0 uM CEM 91.1 89.56 1 1 1 TDKYRLHL (SEQ ID NO.) 54 MGYQKKLRSM  1.0 uM CEM 83.08 77.31 1 1 1 TDKYRLHL (SEQ ID NO.) 54 MGYQKKLRSM  1.0 uM CEM 110.43 114.34 1 1 1 TDKYRLHL (SEQ ID NO.) 55 MGYQKKLRSM  1.0 uM CEM 18.58 39.83 0.2 1 0.2 TDKYRLHLSV (SEQ ID NO.) 55 MGYQKKLRSM  1.0 uM CEM 43.3 72.73 0.2 1 0.2 TDKYRLHLSV (SEQ ID NO.) 56 MGYQKKLRSM  1.0 um CEM 33.7 31.5 0.2 1 0.2 TDKYRLHLSV (SEQ ID NO.) 56 MGYQKKLRSM  1.0 um CEM 64.22 70.2 1 1 1 TDKYRLHLSV (SEQ ID NO.) 59 MGYQKKLRSM  1.0 um CEM 51.62 59.79 1 1 1 TDK (SEQ ID NO.) 59 MGYQKKLRSM  1.0 uM CEM 68.96 84.52 1 1 1 TDK (SEQ ID NO.) 69 SGYQKKLRSST  1.0 uM CEM 100 93.13 25 25 1 D (SEQ ID NO.)

TABLE 19 CXCR4 i2 loop Chemotaxis data SUPB-15 cells Peak AUC Max Test Peak Comp. (% of (% of Comp. Control Peak # Sequence Conc vehicle) vehicle) (nM) (nM) Ratio 83 HATNSQRPRK 1.0 uM 126.36 110.06 5 5 1 LLAEKV (SEQ ID NO.) 82 HATNSQRPRK 1.0 uM 124.56 126.31 1 5 0.2 LLAEK (SEQ ID NO.) 81 HATNSQRPRK 1.0 uM 79.85 76.46 5 25 0.2 LLAE (SEQ ID NO.) 80 HATNSQRPRK 1.0 uM 102.2 69.02 5 25 0.2 LLA (SEQ ID NO.) 79 HATNSQRPRK 1.0 uM 109.36 109.68 5 25 0.2 L (SEQ ID NO.) 78 VHATNSQRPR 1.0 uM 71.85 72.31 5 25 0.2 KLLA (SEQ ID NO.) 77 DRYLAIVHAT 1.0 uM 42.24 56.21 0.2 1 0.2 NSQRPRKLL (SEQ ID NO.) 77 DRYLAIVHAT 1.0 uM 31.64 55.59 0.2 0.2 1 NSQRPRKLL (SEQ ID NO.) 76 DRYLAIVHAT 1.0 uM 52.16 54.04 0.2 0.2 1 NSQRPRKLL (SEQ ID NO.) 76 DRYLAIVHAT 1.0 uM 8.95 9.03 1 1 1 NSQRPRKLL (SEQ ID NO.) 75 VHATNSQRPR 1.0 uM 46.73 52.32 1 0.2 5 KLLAEKVVY (SEQ ID NO.) 75 VHATNSQRPR 1.0 uM 47.91 64.15 0.2 1 0.2 KLLAEKVVY (SEQ ID NO.) 74 DRYLAIVHAT 1.0 uM 90.39 91.29 5 5 1 NSQRPRKLL (SEQ ID NO.) 74 DRYLAIVHAT 1.0 uM 77.13 75.81 5 1 5 NSQRPRKLL (SEQ ID NO.)

TABLE 20 CXCR4 i3 loop Chemotaxis data CEM cells AUC Max Peak Test Peak (% of (% of Compound Control Peak Comp. # Sequence Conc vehicle) vehicle) (nM) (nM) Ratio 87 HSKGHQKR  1.0 uM 52.64 76.1 0.2 1 0.2 KQALK (SEQ ID NO.) 88 SKLSHSKGH  3.0 uM 116.49 114.49 0.8 0.8 1 QKRKALKT TVIL (SEQ ID NO. 253) 88 SKLSHSKGH  1.0 uM 143.61 131.59 0.8 0.8 1 QKRKALKT TVIL (SEQ ID NO. 253) 88 SKLSHSKGH  0.3 uM 131.2 113.68 0.2 0.8 0.2 QKRKALKT TVIL (SEQ ID NO. 253) 88 SKLSHSKGH  0.1 uM 183.19 157.79 0.03 0.8 0.04 QKRKALKT TVIL (SEQ ID NO. 253) 88 SKLSHSKGH 0.03 uM 226.59 202.16 0.03 0.8 0.04 QKRKALKT TVIL (SEQ ID NO. 253) 88 SKLSHSKGH 0.01 uM 172.33 156.08 0.03 0.8 0.04 QKRKALKT TVIL (SEQ ID NO. 253) 89 KLSHSKGHQ  1.0 uM 37.55 59.71 1 25 0.04 KRKALKTT VIL (SEQ ID NO. 249) 90 KLSHSKGHQ  3.0 uM 152.75 114.49 0.16 0.16 1 KRKALKTT V (SEQ ID NO. 248) 90 KLSHSKGHQ  1.0 uM 153.95 131.59 0.16 0.16 1 KRKALKTT V (SEQ ID NO. 248) 90 KLSHSKGHQ  0.3 uM 129.83 113.68 0.16 0.16 1 KRKALKTT V (SEQ ID NO. 248) 90 KLSHSKGHQ  0.1 uM 175.95 157.79 0.03 0.16 0.2 KRKALKTT V (SEQ ID NO. 248) 90 KLSHSKGHQ 0.03 uM 217.53 202.16 0.16 0.16 1 KRKALKTT V (SEQ ID NO. 248) 90 KLSHSKGHQ 0.01 uM 171.8 156.08 0.16 0.16 1 KRKALKTT V (SEQ ID NO. 248) 90 KLSHSKGHQ  1.0 uM 66.71 76.8 0.2 25 0.01 KRKALKTT V (SEQ ID NO. 248) 92 KLSHSKGHQ  3.0 uM 183.65 175.7 0.8 0.8 1 KRKALK (SEQ ID NO.) 92 KLSHSKGHQ  1.0 uM 196.33 163.91 0.16 0.8 0.2 KRKALK (SEQ ID NO.) 92 KLSHSKGHQ  0.3 uM 179.77 165.35 0.16 0.8 0.2 KRKALK (SEQ ID NO.) 92 KLSHSKGHQ  0.1 uM 173.69 169.49 0.16 0.8 0.2 KRKALK (SEQ ID NO.) 92 KLSHSKGHQ 0.03 uM 200.49 198.29 0.16 0.8 0.2 KRKALK (SEQ ID NO.) 92 KLSHSKGHQ 0.01 uM 157.79 155.72 0.16 0.8 0.2 KRKALK (SEQ ID NO.) 92 KLSHSKGHQ  1.0 uM 32.08 77.15 0.2 1 0.2 KRKALK (SEQ ID NO.) 93 KLSHSKGHQ  1.0 uM 15.86 54.8 0.2 1 0.2 KRKAL (SEQ ID NO.) 94 KLSHSKGHQ  1.0 uM 65.28 80.48 1 1 1 KRKA (SEQ ID NO.) 95 LSHSKGHQK  1.0 uM 77.47 92.11 1 1 1 RKALK (SEQ ID NO.) 96 SHSKGHQK  1.0 uM 34.22 63.12 1 1 1 RKALK (SEQ ID NO.) 97 HSKGHQKR  1.0 uM 48.9 54.67 1 5 0.2 KALKT (SEQ ID NO.) 99 HSKGHQKR  1.0 uM 44.95 64.52 0.2 1 0.2 KALKTTV (SEQ ID NO.) 100 HSKGHQKR  1.0 uM 49.31 49.84 0.2 5 0.04 KALKKTTVI (SEQ ID NO.) 101 SKLSHSKGH  1.0 uM 75.55 74.92 1 1 1 QKRKALK (SEQ ID NO.) 102 IIISKLSHSK  1.0 um 0 0.24 1 GHQKRKAL KT (SEQ ID NO.) 103 IIISKLSHSK  1.0 uM 26.32 24.45 1 1 1 GHQKRKAL KT (SEQ ID NO.) 104 IIISKLSHSK  1.0 uM 36.4 56.39 0.2 1 0.2 GHQKRKAL KT (SEQ ID NO.) 105 KLSHSKGHQ  1.0 uM 23.79 42.91 0.2 1 0.2 KRKALKTT VIL (SEQ ID NO. 249)

TABLE 21 CXCR4 i4 Loop CHTX data CEM cells Peak AUC Max Test Peak (% of (% of Comp. Control Peak Cmpd # Sequence Conc Vehicle) Vehicle) (nM) (nM) Ratio 116 GAKFKTSAQH 1.0 uM 65.28 80.48 1 1 1 ALTSVR (SEQ ID NO.) 115 GAKFKTSAQH 1.0 uM 77.47 92.11 1 1 1 ALTSVSRGSSL K (SEQ ID NO.) 114 GAKFKTSAQH 1.0 uM 34.22 63.12 1 1 1 ALTSVSRGSSL KILSK (SEQ ID NO.) 112 GAKFKTSAQH 1.0 uM 48.9 54.67 1 5 0.2 ALTSVSRGSSL KILSGGK (SEQ ID NO.) 110 GAKFKTSAQH 1.0 uM 40.98 42.08 5 5 1 ALTSVSRGSSL KILSKGKRGG SCFH (SEQ ID NO.) 109 GAKFKTSAQH 1.0 uM 49.31 49.84 0.2 5 0.04 ALTSVSRGSSL KILSKGKRGG HSSVST (SEQ ID NO.) 108 GAKFKTSAQH 1.0 uM 89.47 83.94 25 5 5 ALTSVSRGSSL KILSKGKRG (SEQ ID NO.) 108 GAKFKTSAQH 1.0 uM 89.47 83.94 25 5 5 ALTSVSRGSSL KILSKGKRG (SEQ ID NO.) 107 GAKFKTSAQH 1.0 uM 57.34 49.48 25 5 5 ALTSVSRGSSL KILSKGKRGG HSSVST (SEQ ID NO.)

Compounds with varying biological activities at the CXCR4 receptor have been identified. These include positive allosteric modulating activity, negative allosteric modulating activity, and allosteric agonists. Compounds exhibiting negative allosteric modulating activity at the CXCR4 receptor are evidenced by their ability to inhibit chemoattraction in response to SDF1-a induced chemoattraction. Compound receptor modulators are capable of modifying CXCR4 dependent activity in several characteristic patterns. In FIGS. 1-4, these activities are present.

One such phenotype is left- or right-shifting of the SDF1-a dependent chemotactic response. An example of this response is shown by Compound 43. In this case, 1 uM of Compound 43 induces a left shift of the SDF1-a mediated chemotactic response.

Another phenotype is positive allosteric modulation of the SDF1-a dependent chemotactic response. An example of this response is shown with Compound No. 44. In this case, 30 nM of Compound 88 induces a positive SDF1-a mediated chemotactic response (i.e., the larger RFU response indicates that a greater number of cells migrate toward SDF1a in the presence of Compound 44).

In another example, Compound 44 negatively modulates the SDF1-a induced chemotactic response in CEM cells as evidenced by the lower raw relative fluorescent units (RFU) which reflects the number of cells migrating toward an SDF1a gradient. The lower RFU response, the fewer migrating cells.

Compounds with allosteric agonist activity are evidenced by their ability to induce CXCR4 dependent calcium mobilization (FIG. 5) and/or chemoattraction of leukocytes expressing CXCR4 (FIG. 6). Like the endogenous agonist SDF1-a activity, these CXCR4 agonists exhibit a bell-shaped activity curve with respect to chemoattraction.

HTRF cAMP Assay and IP-One Assay (Cisbio)

HTRF (homogeneous time resolved fluorescence) is a technology developed by Cisbio Bioassays based on TR-FRET (time-resolved fluorescence resonance energy transfer). Cisbio Bioassays has developed a wide selection of HTRF-based assays compatible with whole cells, thereby enabling functional assays run under more physiological conditions. cAMP kits are based on a competitive immunoassay using cryptate-labeled anti-cAMP antibody and d2-labeled cAMP. This assay allows the measurement of increase in intracellular cAMP upon Gs-coupled receptor activation as well as decrease in forskolin stimulated increase in cAMP upon Gi-coupled receptor activation. The IP-One assays are competitive immunoassays that use cryptate-labeled anti-IP 1 monoclonal antibody and d2-labeled IP1. IP1 is a relatively stable downstream metabolite of IP3, and accumulates in cells following Gq receptor activation.

AlphaScreen Cellular Kinase Assays.

GPCR activation results in modulation of downstream kinase systems and is often used to probe GPCR function and regulation. TGR Bioscience and PerkinElmer have developed Surefire cellular kinase assay kits that are HTS capable and useful in screening kinase regulation. Such kits enable the monitoring of Gi regulated downstream kinases like ERK1/2. The assay allows the measurement of increases in ERK1/2 kinase phosphorylation upon Gi coupled receptor (e.g., CXCR4) activation and this signal in turn can be used to assay Gi coupled receptor modulator. Similar kits are also available to assay other pathway dependent signaling kinases such as MAP and BAD.

In Vivo Assays

Animal models are currently available for in vivo validation of novel therapeutics targeting the CXCR4/SDF-1 signaling axis include the mouse air pouch WBCs recruitment model, the PMN mobilization model, the HPCs mobilization model and BM transplantation models including NOD/SCID mice repopulation model.

In the mouse air pouch WBCs recruitment model, the air pouch is formed by 2 subcutaneous injections (on day 0 and day 3) of 3 ml of sterile air. On day 6 mice receive an injection of 1 ml of SDF-1 solution into the formed air pouch. Six or 24 hours later WBCs recruited to the air pouch are recovered and WBCs subsets are analyzed using differential cell count and Flow Cytometry. In this model the concentration of SDF-1 in air pouch is controlled by an investigator.

The other animal models that are widely used for the in vivo validation of novel CXCR4 antagonists are PMNs mobilization'model and hematopoietic progenitor's cells (HPCs) mobilization models. These two models are very similar and they exploit the fact that bone marrow niche express high level of SDF-1. Bone marrow SDF-1 interacts with the CXCR4 on bone marrow cells and constitutively activates it. This SDF-1/CXCR4 interaction is critical for the retention of HPCs and immature PMNs within the bone marrow. Disruption of this interaction causes release of PMNs and HPCs into peripheral blood where they can be readily detected and counted using differential cell counter (for PMNs), Flow Cytometry and colony forming units assay (for HPCs). In contrast to the air pouch model, in this model the concentration of SDF-1 is physiological. In addition, PMNs/HPCs mobilization models do not require preliminary preparation of animals for actual experiment as is the case in air pouch WBCs recruitment model.

Bone marrow transplantation models allow assessing long term engraftment potential of mobilized into peripheral blood hematopoietic stem cells (HSCs). The donor cells can be of either mouse or human origin like in the NOD/SCID mice repopulation model. In long term repopulation model dilutions of donor blood cells compete with the recipient marrow cells for engraftment in lethally irradiated recipients. This model is relatively long and takes up to 4 months to accomplish.

Recently hematological malignancies such as Acute Myeloid Leukemia (AML) were recognized as potential indications for anti-CXCR4 therapy. Preclinical data suggests that dislodging of malignant cells from bone marrow environment using CXCR4 antagonists significantly improves survival of animals and outcome of chemotherapy. Several animal models of chemosensitization were developed. They are based on the induction of AML following adoptive transfer of malignant cells such APL cells from mCG-PML-PARα mice, A20 cells, or Ba/F3 cells. To facilitate the detection of malignant cells genes encoding fluorescent proteins or luciferase are introduced into them. The progression of AML and efficacy of anti-AML chemotherapy is assessed using FACS analysis of cells from peripheral blood, spleen and bone marrow. In addition, whole body in vivo bioluminescence imaging allows quantitatation of the effect of CXCR4 antagonists on anti-AML therapy in individual animal over time.

Results

Results are shown in FIG. 7-12.

CXCR-4 compound antagonists/modulators mobilize white blood cells in vivo (mouse model) with efficacy similar to AMD3100 (Mozobil) See FIG. 7. Upon analysis of cell types in peripheral blood it was found that CXCR4 receptor compounds are predominately mobilizing polymorphonuclear lymphocytes (See FIG. 9).

CXCR-4 compound antagonists/modulators are active in mobilizing bone marrow progenitor cells with efficacy similar to AMD3100 (Mozobil). This was demonstrated in a mouse model of progenitor cell mobilization. See FIG. 10. In this assay, DBA/2 mice, male, 10 weeks old, n=4/group; vehicle (10% PEG, 0.1 ml; AMD3100 (2 μmol/kg, in PBS); ATI-2346 (2 μmol/kg, 10% PEG, 0.1 ml). WBCs harvested from 150 ml of blood, premixed with 3 ml of Methocult medium. CFU-GM colonies were scored at day 12.

CXCR-4 compound agonists are also active in mobilizing both neutrophils and bone marrow progenitor cells. The CXCR4 agonist SDF1a has similarly been shown to mobilize bone marrow progenitor cells and hypothesized to occur by establishing an additional chemotactant gradient in the blood following intravenous injection to oppose the natural retentive function of SDF1a in the bone marrow. CXCR4 compound agonists also likely function in this way to mobilize BMPC. An example of Compound 38 agonist data are shown in FIG. 8.

The effects of 10 μmol/kg CXCR-4 receptor compound 43 and CXCR4 compound AMD3100 on PMN recruitment in BALB/c mice following subcutaneous injection are shown in FIG. 11.

The effects of 10 μmol/kg CXCR-4 receptor compound 43 and CXCR4 compound AMD3100 on lymphocyte recruitment in BALB/c mice following subcutaneous injection are shown in FIG. 12.

The teachings of all patents, published applications and references cited herein are incorporated by reference in their entirety.

While this invention has been particularly shown and described with references to example embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims. 

1. A compound represented by Formula A: T-L-X₁-X₂-X₃-X₄-X₅-X₆-X₇-X₈-X₉-X₁₀-X₁₁-X₁₂-X₁₃-X₁₄-X₁₅-X₁₆-X₁₇-X₁₈-X₁₉-X₂₀-X₂₁-X₂₂-X₂₃-X₂₄—R₁; or a pharmaceutically acceptable salt thereof, wherein: L is a linking moiety represented by C(O) and bonded to the N terminal nitrogen of X₁ or the next present amino acid residue if X₁ is absent; T is a lipophilic tether moiety bonded to L; and R₁ is OR₂ or N(R₂)₂, each R₂ is independently H or alkyl, wherein at least three contiguous X₁-X₂₄ amino acid residues are present, and wherein: X₁ is a valine residue or absent X₂ is a isoleucine residue or absent, X₃ is a leucine residue or absent, X₄ is a valine residue, a glycine residue or absent, X₅ is a methionine residue, a isoleucine residue, a leucine residue, a norleucine residue, a serine residue, an alanine residue, a d-methionine residue, a d-serine residue, or absent, X₆ is a glycine residue, an alanine residue, a histidine residue, a lysine residue or absent, X₇ is a tyrosine residue, an alanine residue, a d-tyrosine residue, an arginine residue or absent X₈ is a glutamine residue, an alanine residue, a d-glutamine residue, a methionine residue, a threonine residue, or a lysine residue or absent, X₉ is a lysine residue, a d-lysine residue, a alanine residue or absent, X₁₀ is a lysine residue, a d-lysine residue, a leucine residue, a threonine residue, an alanine residue or absent, X₁₁ is a leucine residue, a d-leucine residue, an alanine residue, an isoleucine residue, a serine residue, a cysteine residue, an arginine residue or absent, X₁₂ is an arginine residue, a d-arginine residue, an alanine residue, a leucine residue, an aspartic acid residue, a cysteine residue, or absent, X₁₃ is a serine residue, a d-serine residue, an alanine residue, a tyrosine residue or absent, X₁₄ is a methionine residue, a serine residue, a leucine residue, an isoleucine residue, a norleucine residue, an alanine residue, a d-methionine residue, an aspartic acid residue, or absent, X₁₅ is a threonine residue, a d-threonine residue, a arginine residue, a glycine residue, an alanine residue or absent, X₁₆ is an aspartic acid residue, and -aspartic acid residue, an alanine residue, an arginine residue, a lysine residue or absent, X₁₇ is a methionine residue, a lysine residue, a histidine residue, a leucine residue, a cysteine residue or absent, X₁₈ is a tyrosine residue, a glutamine residue, a leucine residue, a lysine residue, a cysteine residue or absent, X₁₉ is an arginine residue, a tyrosine residue, a serine residue, a methionine residue or absent, X₂₀ is a leucine residue, a isoleucine residue, an arginine residue, or a valine residue or absent, X₂₁ is a histidine residue, a lysine residue, a leucine residue or absent, X₂₂ is a leucine residue, a tyrosine residue or absent, X₂₃ is an arginine residue, a serine residue or absent, and X₂₄ is a valine residue, a leucine residue or absent; wherein when X₁-X₄ and X₁₇-X₂₄ are absent and X₅ is a methionine residue, then at least one of the amino acids of X₆-X₁₆ is an alanine residue or a d-amino acid, and wherein when X₁-X₆ and X₁₇-X₂₄ are absent and X₇ is a tyrosine residue then at least one of the amino acids of X₈-X₁₆ is an alanine residue, d-amino acid or a serine residue.
 2. The compound of claim 1, wherein X₁-X₄ and X₁₇-X₂₄ are absent and wherein: X₅ is a methionine residue, a d-methionine residue, an isoleucine residue, a leucine residue, a serine residue, an alanine residue, or d-a methionine residue, X₆ is a glycine residue or an alanine residue, X₇ is a tyrosine residue, an alanine residue, or a d-tyrosine residue, X₈ is a glutamine residue, an alanine residue or a d-glutamine residue, X₉ is a lysine residue, a d-lysine residue, or an alanine residue, X₁₀ is a lysine residue, a d-lysine residue, or an alanine residue, X₁₁ is a leucine residue, a d-leucine residue, or an alanine residue, X₁₂ is an arginine residue, a d-arginine residue, or an alanine residue, X₁₃ is a serine residue, a d-serine residue, or an alanine residue, X₁₄ is a methionine residue, a serine residue, a leucine residue, an isoleucine residue, an alanine residue, or a d-methionine residue, X₁₅ is a threonine residue, a d-threonine residue, or an alanine residue, and X₁₆ is aspartic acid residue, a d-aspartic acid residue, or an alanine residue, or an arginine residue.
 3. The compound of claim 1, wherein X₁-X₄ and X₂₁-X₂₄ are absent, and wherein: X₅ is a methionine residue, a d-methionine residue an alanine residue or a glycine residue, X₆ is a glycine residue or an alanine residue, X₇ is a tyrosine residue, a d-tyrosine residue, or an alanine residue, X₈ is a glutamine residue, d-glutamine residue, or an alanine residue, X₉ is a lysine residue, a d-lysine residue or an alanine residue, X₁₀ is a lysine residue, a d-lysine residue or an alanine residue, X₁₁ is a leucine residue, a d-leucine residue, an alanine residue, a proline residue or a d-proline residue, X₁₂ is an arginine residue, a d-arginine residue, an alanine residue, a proline residue or d-proline residue, X₁₃ is a serine residue, a d-serine residue, an alanine residue, a proline residue or a d-proline residue, X₁₄ is a methionine residue, an alanine residue, a d-methionine residue, a d-proline residue, a glycine residue, a histidine residue, or noreleucine residue X₁₅ is a threonine residue, a d-threonine residue, a d-proline residue, a proline residue or an alanine residue, X₁₆ is an aspartic acid residue, a d-aspartic acid residue, or an alanine residue, X₁₇ is a lysine residue, a d-lysine residue or an alanine residue, X₁₈ is a tyrosine residue, a d-tyrosine residue, or an alanine residue, X₁₉ is an arginine residue, a lysine residue, or a d-arginine residue, and X₂₀ is a leucine residue, a d-leucine residue, an alanine residue, a noreleucine residue, an isoleucine residue or a valine residue.
 4. The compound of claim 1, wherein X₁-X₈ are absent, and wherein: X₉ is a lysine residue, a d-lysine residue or an alanine residue, X₁₀ is a lysine residue, a d-lysine residue or an alanine residue, X₁₁ is a leucine residue, a d-leucine residue or an alanine residue, X₁₂ is an arginine residue, a d-arginine residue or an alanine residue, X₁₃ is a serine residue, a d-serine residue or an alanine residue, X₁₄ is a methionine residue, a d-methionine residue, a norleucine residue or an alanine residue, X₁₅ is a threonine residue, a d-threonine residue, or an alanine residue, X₁₆ is an aspartic acid residue, a d-aspartic acid residue, or an alanine residue, X₁₇ is a lysine residue, a d-lysine residue or an alanine residue, X₁₈ is a tyrosine residue, a d-tyrosine residue, an alanine residue or absent, X₁₉ is an arginine residue, a d-arginine, an alanine residue or absent, X₂₀ is leucine residue, a d-leucine, an alanine or absent, X₂₁ is a histidine residue, a d-histidine residue, a d-serine residue, an alanine residue or absent, X₂₂ is leucine residue, isoleucine residue or absent, X₂₃ is a serine residue or absent, and X₂₄ is a valine residue or absent.
 5. The compound of claim 4, wherein X₂₂, X₂₃ and X₂₄ are absent.
 6. The compound of claim 1, wherein X₁-X₅ and X₂₂-X₂₄ are absent, and wherein: X₆ is a glycine residue or absent, X₇ is a tyrosine residue or absent, X₈ is a glutamine residue or absent, X₉ is a lysine residue or absent, X₁₀ is a lysine residue or absent, X₁₁ is a leucine residue or absent, X₁₂ is an arginine residue or absent, X₁₃ is a serine residue or absent, X₁₄ is a methionine residue or absent, X₁₅ is a threonine residue, X₁₆ is an aspartic acid residue, X₁₇ is a lysine residue, X₁₈ is a tyrosine residue, X₁₉ is an arginine residue, X₂₀ is a leucine residue, and X₂₁ is a histidine residue.
 7. The compound of claim 1, wherein X₁-X₅ and X₂₂-X₂₄ are absent, and wherein: X₆ is a glycine residue, X₇ is a tyrosine residue, X₈ is a glutamine residue, X₉ is a lysine residue, X₁₀ is a lysine residue, X₁₁ is a leucine residue, X₁₂ is an arginine residue, X₁₃ is a serine residue or absent, X₁₄ is a methionine residue or absent, X₁₅ is threonine residue or absent, X₁₆ is an aspartic acid residue or absent, X₁₇ is a lysine residue or absent, X₁₈ is a tyrosine residue or absent, X₁₉ is an arginine residue or absent, X₂₀ is a leucine residue or absent, and X₂₁ is a histidine residue or absent.
 8. The compound of claim 1, wherein X₁-X₅ and X₂₁-X₂₄ are absent, wherein at least seven contiguous amino acid residues are present, and wherein: X₆ is a glycine residue or absent, X₇ is a tyrosine residue or absent, X₈ is a glutamine residue or absent, X₉ is a lysine residue or absent, X₁₀ is a lysine residue or absent, X₁₁ is a leucine residue or absent, X₁₂ is a an arginine residue or absent, X₁₃ is a serine residue or absent, X₁₄ is a methionine residue or absent X₁₅ is a threonine residue or absent, X₁₆ is an aspartic acid residue or absent, X₁₇ is a lysine residue or absent, X₁₈ is a tyrosine residue or absent, X₁₉ is an arginine residue or absent, and X₂₀ is a leucine residue or absent.
 9. The compound of claim 1, wherein X₁ and X₂ are absent, X₃ is a leucine residue or absent, X₄ is a glycine residue or absent, X₅ is a serine residue, a d-serine residue or absent, X₆ is a glycine residue, a histidine residue, a lysine residue or absent, X₇ is a tyrosine residue or an arginine residue, X₈ is a glutamine residue, or a methionine residue, X₉ is a lysine residue, X₁₀ is a lysine residue or a threonine residue, X₁₁ is a leucine residue or a serine residue, X₁₂ is an arginine residue, or a leucine residue, X₁₃ is a serine residue, or a tyrosine residue, X₁₄ is a serine residue, a leucine residue, an isoleucine residue, or an aspartic acid residue, X₁₅ is a threonine residue or a glycine residue, X₁₆ is an aspartic acid residue or an arginine residue, X₁₇ is a methionine residue or absent, X₁₈ is a glutamine residue or absent, X₁₉ is, a tyrosine residue or absent, X₂₀ is a leucine residue, a isoleucine residue, an arginine residue, a valine residue or absent, X₂₁ is a histidine residue, a lysine residue, or absent, X₂₂ is a leucine residue or absent, X₂₃ is a serine residue or absent, and X₂₄ is a valine residue or absent.
 10. The compound of claim 1 selected from any one of Compound Nos. 1-73 and 117-194.
 11. The compound of claim 10 selected from any one of Compound Nos. 1-73.
 12. The compound of claim 10 selected from any one of Compound Nos. 117-194.
 13. A compound of claim 1 selected from:

or a pharmaceutically acceptable salt thereof.
 14. A compound of claim 1 having the following structural formula;

or a pharmaceutically acceptable salt thereof.
 15. A compound represented by Formula B or a pharmaceutically acceptable salt thereof: T-L-Y₁-Y₂-Y₃-Y₄-Y₅-Y₆-Y₇-Y₈-Y₉-Y₁₀-Y₁₁-Y₁₂-Y₁₃-Y₁₄-Y₁₅-Y₁₆-Y₁₇-Y₁₈-Y₁₉-Y₂₀-Y₂₁-Y₂₂-Y₂₃-Y₂₄-Y₂₅-R₁; wherein L is a linking moiety represented by C(O) and bonded to the N terminal nitrogen of Y₁ or the next present amino acid residue if Y₁ is absent; T is a lipophilic tether moiety bonded to L; and R₁ is OR₂ or N(R₂)₂, each R₂ is independently H or alkyl, wherein at least three contiguous Y₁-Y₂₅ amino acid residues are present and wherein at least one of Y₁-Y₂₂ is absent, a d-amino acid residue or an alanine residue, and wherein: Y₁ is an aspartic acid residue, a d-aspartic acid residue, an alanine residue or absent, Y₂ is an arginine residue, a d-arginine residue, an alanine residue or absent, Y₃ is a tyrosine residue, a d-tyrosine residue, an alanine residue or absent, Y₄ is a leucine residue a d-leucine residue, an alanine residue or absent, Y₅ is an alanine residue, a d-alanine residue or absent, Y₆ is an isoleucine residue, a d-isoleucine residue, an alanine residue or absent, Y₇ is a valine residue, a d-valine acid residue, an alanine residue or absent, Y₈ is a histidine residue a d-histidine residue, an alanine residue or absent, Y₉ is an alanine residue, a d-alanine residue or absent, Y₁₀ is a threonine residue, a d-threonine residue, an alanine residue or absent, Y_(1l) is an asparagine residue, a d-asparagine residue, an alanine residue or absent, Y₁₂ is a serine residue, a d-serine residue, an alanine residue or absent, Y₁₃ is a glutamine residue, a d-glutamine residue, an alanine residue or absent, Y₁₄ is an arginine residue, a d-arginine residue, an alanine residue or absent, Y₁₅ is a proline residue, a d-proline residue, an alanine residue or absent, Y₁₆ is an arginine residue, a d-arginine residue, an alanine residue or absent, Y₁₇ is a lysine residue, a d-lysine residue, an alanine residue or absent, Y₁₈ is a leucine residue, a d-leucine residue, an alanine residue or absent, Y₁₉ is a leucine residue, a d-leucine residue, an alanine residue or absent, Y₂₀ is an alanine residue, a d-alanine, an isoleucine residue, a d-isoleucine residue, an arginine residue, a d-arginine residue, a valine residue, a d-valine or absent, Y₂₁ is a glutamic acid residue, a d-glutamic acid residue, an alanine residue, a d-alanine residue or absent, Y₂₂ is a lysine residue, a d-lysine residue, an alanine residue or absent, Y₂₃ is a valine residue, a d-valine residue or absent, Y₂₄ is a valine residue, a d-valine residue or absent, and Y₂₅ is a tyrosine residue, a d-tyrosine residue or absent.
 16. The compound of claim 15, wherein Y₂₃-Y₂₅ are absent, and wherein: Y₁ is an aspartic acid residue, Y₂ is an arginine residue, Y₃ is a tyrosine residue, Y₄ is a leucine residue, Y₅ is an alanine, Y₆ is an isoleucine residue, Y₇ is a valine residue, Y₈ is a histidine residue, Y₉ is an alanine or absent, Y₁₀ is a threonine or absent, Y₁₁ is an asparagine or absent, Y₁₂ is a serine residue or absent, Y₁₃ is a glutamine residue or absent, Y₁₄ is an arginine residue or absent, Y₁₅ is a proline residue or absent, Y₁₆ is an arginine residue or absent, Y₁₇ is a lysine residue or absent, Y₁₈ is a leucine residue, Y₁₉ is a leucine residue, Y₂₀ is an alanine residue or absent, Y₂₁ is a glutamic acid residue or absent, and Y₂₂ is a lysine residue or absent.
 17. The compound of claim 15, wherein Y₁ and Y₂₃-Y₂₅ are absent, and wherein: Y₂ is an arginine residue or absent, Y₃ is a tyrosine residue or absent, Y₄ is a leucine residue or absent, Y₅ is an alanine residue or absent, Y₆ is an isoleucine residue or absent, Y₇ is a valine residue or absent, Y₈ is a histidine residue or absent, Y₉ is an alanine or absent, Y₁₀ is a threonine or absent, Y₁₁ is an asparagine or absent, Y₁₂ is a serine residue or absent, Y₁₃ is a glutamine residue or absent, Y₁₄ is an arginine residue or absent, Y₁₅ is a proline residue or absent, Y₁₆ is an arginine residue or absent, Y₁₇ is a lysine residue, Y₁₈ is a leucine residue, Y₁₉ is a leucine residue, Y₂₀ is an alanine residue, Y₂₁ is a glutamic acid residue, and Y₂₂ is a lysine residue.
 18. The compound of claim 15, wherein Y₂₃-Y₂₅ are absent and wherein seven contiguous Y₁-Y₂₂ amino acid residues are present, and wherein: Y₁ is an aspartic acid residue or absent, Y₂ is an arginine residue or absent, Y₃ is a tyrosine residue or absent, Y₄ is a leucine residue or absent, Y₅ is an alanine residue or absent, Y₆ is an isoleucine residue or absent, Y₇ is a valine residue or absent, Y₈ is a histidine residue or absent, Y₉ is an alanine residue or absent, Y₁₀ is a threonine residue or absent, Y₁₁ is an asparagine residue or absent, Y₁₂ is a serine residue or absent, Y₁₃ is a glutamine residue or absent, Y₁₄ is an arginine residue or absent; Y₁₅ is a proline residue or absent, Y₁₆ is an arginine residue or absent, Y₁₇ is a lysine residue or absent, Y₁₈ is a isoleucine residue or absent, Y₁₉ is a leucine residue or absent, Y₂₀ is an alanine residue or absent, Y₂₁ is a glutamic acid residue or absent, and Y₂₂ is a lysine residue or absent.
 19. The compound of claim 15, wherein Y₁-Y₆ are absent, and wherein: Y₇ is a valine residue or absent, Y₈ is a histidine residue, Y₉ is a alanine residue, Y₁₀ is a threonine residue, Y₁₁ is an asparagine residue, Y₁₂ is a serine residue, Y₁₃ is a glutamine residue, Y₁₄ is an arginine residue, Y₁₅ is a proline residue, Y₁₆ is an arginine residue, Y₁₇ is a lysine residue, Y₁₈ is a leucine residue, Y₁₉ is a leucine residue or absent, Y₂₀ is an alanine residue or absent, Y₂₁ is a glutamic acid or absent, Y₂₂ is a lysine residue or absent, Y₂₃ is a valine lysine residue or absent, Y₂₄ is a valine residue or absent, and Y₂₅ is a tyrosine residue or absent.
 20. The compound of claim 11 selected from any one of Compound Nos. 74-83.
 21. A compound represented by Formula C or a pharmaceutically acceptable salt thereof: T-L-W₁-W₂-W₃-W₄-W₅-W₆-W₇-W₈-W₉-W₁₀-W₁₁-W₁₂-W₁₃-W₁₄-W₁₅-W₁₆-W₁₇-W₁₈-W₁₉-W₂₀-W₂₁-W₂₂-W₂₃-W₂₄-W₂₅-W₂₆-W₂₇-W₂₈-W₂₉-W₃₀-W₃₁-W₃₂-R₁; wherein L is a linking moiety represented by C(O) and bonded to W₁ at an N terminal nitrogen of W₁ or the next present amino acid residue if W₁ is absent; T is a lipophilic tether moiety bonded to L; R₁ is OR₂ or N(R₂)₂, each R₂ is independently H or alkyl, wherein at least three contiguous W₁-W₃₂ are present, and wherein: W₁ is an isoleucine residue, a d-isoleucine residue, an alanine residue or absent, W₂ is isoleucine residue, a d-isoleucine residue, an alanine residue or absent, W₃ is isoleucine residue, a d-isoleucine residue, an alanine residue or absent, W₄ is a serine residue, a d-serine residue, an alanine residue or absent, W₅ is a lysine residue, a d-lysine residue, an alanine residue or absent, W₆ is a leucine residue, a histidine residue, a d-leucine residue, an alanine residue or absent, W₇ is a serine residue, a d-serine residue, an alanine residue or absent, W₈ is a histidine residue, a d-histidine residue, an alanine residue or absent, W₉ is a serine residue, a d-serine residue, an alanine residue a lysine residue, or absent, W₁₀ is a lysine residue, a d-lysine residue, an alanine residue, a leucine residue, an isoleucine residue or absent, W₁₁ is glycine residue, a d-glycine residue, an alanine residue or absent, W₁₂ is a histidine residue, a d-histidine residue, an alanine residue a tyrosine residue or absent, W₁₃ is a glutamine residue, a d-glutamine residue, an alanine residue or absent, W₁₄ is a lysine residue, a d-lysine residue, an alanine residue or absent; W₁₅ is an arginine residue, a d-arginine residue, an alanine residue, a lysine residue or absent, W₁₆ is a lysine residue, a d-lysine residue, an alanine residue, a leucine residue or absent, W₁₇ is an alanine, d-alanine, an arginine residue or absent, W₁₈ is a leucine residue, a d-leucine residue, an alanine residue, a serine residue or absent, W₁₉ is a lysine residue, a d-lysine residue, an alanine residue, a leucine residue, an isoleucine residue or absent, W₂₀ is threonine, a d-threonine residue, an alanine residue leucine residue or absent, W₂₁ is threonine, a d-threonine residue, an alanine residue a lysine residue or aspartic acid or absent, W₂₂ is a valine, a d-valine residue, an alanine residue or absent, W₂₃ is isoleucine residue, a d-isoleucine residue, an alanine residue a serine residue or absent, W₂₄ is leucine residue, a d-leucine residue, an alanine residue an arginine residue or absent, W₂₅ is a lysine residue, a d-lysine residue, an alanine residue or absent, W₂₆ is a valine residue, a d-valine residue, an alanine residue or absent, W₂₇ is a lysine residue, a d-lysine residue, an alanine residue or absent, W₂₈ is a serine residue a d-serine residue, an alanine residue or absent, W₂₉ is a glycine residue, a d-glycine residue, an alanine residue or absent, W₃₀ is a threonine residue, a d-threonine residue, an alanine residue or absent, W₃₁ is a leucine residue, a d-leucine residue, an alanine residue or absent, W₃₂ is a lysine residue, a d-lysine residue, an alanine residue or absent, wherein when W₂₀-W₃₂ is absent at least one of W₁-W₂₃ is also absent and wherein when W₁-W₇ and W₂₀-W₃₂ is absent, at least one of W₈-W₁₉ is absent, a d-amino acid or alanine.
 22. The compound of claim 21, wherein, W₂₄-W₃₂ are absent and wherein: W₁ is an isoleucine residue, W₂ is an isoleucine residue, W₃ is an isoleucine residue, W₄ is a serine residue, W₅ is a lysine residue, W₆ is a leucine residue, W₇ is a serine residue, W₈ is a histidine residue or absent, W₉ is a serine residue, or absent, W₁₀ is a lysine residue or absent, W₁₁ is a glycine residue or absent, W₁₂ is a histidine residue, or absent, W₁₃ is a glutamine residue or absent, W₁₄ is a lysine residue or absent, W₁₅ is an arginine residue or absent, W₁₆ is a lysine residue or absent, W₁₇ is an alanine residue or absent, W₁₈ is a leucine residue or absent, W₁₉ is a lysine residue or absent, W₂₀ is a threonine residue or absent, W₂₁ is a threonine residue or absent, W₂₂ is a valine residue or absent, and W₂₃ is an isoleucine residue or absent.
 23. The compound of claim 21, wherein W₁, W₂₁-W₃₂ are absent and wherein: W₂ is an isoleucine residue or absent, W₃ is an isoleucine residue or absent, W₄ is a serine residue or absent, W₅ is a lysine residue or absent, W₆ is a leucine residue or absent, W₇ is a serine residue or absent, W₈ is a histidine residue or absent, W₉ is a serine residue, or absent, W₁₀ is a lysine residue or absent, W₁₁ is a glycine residue or absent, W₁₂ is a histidine residue, or absent, W₁₃ is a glutamine residue or absent, W₁₄ is a lysine residue, W₁₅ is an arginine residue, W₁₆ is a lysine residue, W₁₇ is an alanine residue, W₁₈ is a leucine residue, W₁₉ is a lysine residue, and W₂₀ is a threonine residue.
 24. The compound of claim 21, wherein seven contiguous amino acid residues of W₁-W₁₉ are present and wherein: W₁ is an isoleucine residue or absent, W₂ is an isoleucine residue or absent, W₃ is an isoleucine residue or absent, W₄ is a serine residue or absent, W₅ is a lysine residue or absent, W₆ is a leucine residue or absent, W₇ is a serine residue or absent, W₈ is a histidine residue or absent, W₉ is a serine residue, or absent, W₁₀ is a lysine residue or absent, W₁₁ is a glycine residue or absent, W₁₂ is a histidine residue, or absent, W₁₃ is a glutamine residue or absent, W₁₄ is a lysine residue or absent, W₁₅ is an arginine residue or absent, W₁₆ is a lysine residue or absent, W₁₇ is an alanine residue or absent, W₁₈ is a leucine residue or absent, and W₁₉ is a lysine residue or absent,
 25. The compound of claim 21, wherein, W₁-W₃ are absent and W₂₅-W₃₂ are absent, and wherein: W₄ is a serine residue or absent, W₅ is a lysine residue or absent, W₆ is a leucine residue or absent, W₇ is a serine residue or absent, W₈ is a histidine residue, W₉ is a serine residue, W₁₀ is a lysine residue, W₁₁ is a glycine residue, W₁₂ is a histidine residue, W₁₃ is a glutamine residue, W₁₄ is a lysine residue, W₁₅ is an arginine residue, W₁₆ is a lysine residue, W₁₇ is alanine or a glutamine residue, W₁₈ is leucine residue alanine or absent, W₁₉ is a lysine residue, leucine residue or absent, W₂₀ is threonine or absent, W₂₁ is threonine or absent, W₂₂ is a valine residue or absent, W₂₃ is isoleucine residue or absent, W₂₄ is leucine residue or absent.
 26. The compound of claim 21 selected from any one of Compound Nos. 84-96.
 27. The compound of claim 21 selected from:

or a pharmaceutically acceptable salt thereof.
 28. A compound represented by Formula D or a pharmaceutically acceptable salt thereof, wherein: T-L-Z₁-Z₂-Z₃-Z₄-Z₅-Z₆-Z₇-Z₈-Z₉-Z₁₀-Z₁₁-Z₁₂-Z₁₃-Z₁₄-Z₁₅-Z₁₆-Z₁₇-Z₁₈-Z₁₉-Z₂₀-Z₂₁-Z₂₂-Z₂₃-Z₂₄-Z₂₅-Z₂₆-Z₂₇-Z₂₈-Z₂₉-Z₃₀-Z₃₁-Z₃₂-Z₃₃-Z₃₄-Z₃₅-Z₃₆-Z₃₇-Z₃₈-Z₃₉-Z₄₀-Z₄₁-Z₄₂-Z₄₃-Z₄₄-Z₄₅-Z₄₆-Z₄₇-R₁; wherein: L is a linking moiety represented by C(O) and bonded to the N terminal nitrogen of Z₁ or the next present amino acid residue if Z₁ is absent; and T is a lipophilic tether moiety bonded to L; R₁ is OR₂ or N(R₂)₂, each R₂ is independently H or alkyl, wherein at least three contiguous Z₁-Z₃₂ amino acid residues are present, and wherein Z₁ is a glycine residue, a d-glycine residue, an alanine residue or absent, Z₂ is an alanine residue a d-alanine residue or absent, Z₃ is a lysine residue, a d-lysine residue, an alanine residue or absent, Z₄ is a phenylalanine residue, a d-phenylalanine residue, an alanine residue or absent, Z₅ is a lysine residue, a d-lysine residue, an alanine residue or absent, Z₆ is a threonine residue, a d-threonine residue, an alanine residue or absent, Z₇ is a serine residue a d-serine residue, an alanine residue or absent, Z₈ is an alanine residue, a d-alanine residue or absent, Z₉ is a glutamine residue, a d-glutamine residue, an alanine residue or absent, Z₁₀ is a histidine residue, a d-histidine residue, an alanine residue or absent, Z₁₁ is an alanine residue, a d-alanine residue or absent, Z₁₂ is a leucine residue, a d-leucine residue, an alanine residue or absent, Z₁₃ is a threonine residue, a d-threonine residue, an alanine residue or absent, Z₁₄ is a serine residue, a d-serine residue, an alanine residue or absent; Z₁₅ is a valine residue, a d-valine residue, an alanine residue or absent, Z₁₆ is a serine residue, a d-serine residue, an alanine residue or absent, Z₁₇ is an arginine residue, a d-arginine residue, an alanine residue or absent, Z₁₈ is a glycine residue, a d-glycine residue, an alanine residue or absent, Z₁₉ is a serine residue, a d-serine residue, an alanine residue or absent, Z₂₀ is a serine residue, a d-serine residue, an alanine residue absent, Z₂₁ is a leucine residue, a d-leucine residue, an alanine residue or absent, Z₂₂ is a lysine residue, a d-lysine residue, an alanine residue or absent, Z₂₃ is a isoleucine residue, a d-isoleucine residue, an alanine residue a serine residue or absent, Z₂₄ is a leucine residue, a d-leucine residue, an alanine residue or absent, Z₂₅ is a serine residue, a d-serine residue, an alanine residue or absent, Z₂₆ is a lysine residue, a d-lysine residue, an alanine residue or absent, Z₂₇ is glycine residue, a d-glycine residue, an alanine residue or absent, Z₂₈ is a lysine residue, a d-lysine residue, an alanine residue or absent, Z₂₉ is an arginine residue, a d-arginine residue, an alanine residue or absent, Z₃₀ is a glycine residue, a d-glycine residue, an alanine residue or absent, Z₃₁ is a glycine residue, a d-glycine residue, an alanine residue or absent, Z₃₂ is a histidine residue, a d-histidine residue, an alanine residue or absent, Z₃₃ is a serine residue, a d-serine residue, an alanine residue or absent, Z₃₄ is a serine residue, a d-serine residue, an alanine residue cysteine, or absent, Z₃₅ is a valine residue, a d-valine residue, an alanine residue a phenylalanine residue, or absent, Z₃₆ is a serine residue, a d-serine residue, an alanine residue a histidine residue or absent, Z₃₇ is a threonine residue, a d-threonine residue, an alanine residue or absent, Z₃₈ is a glutamic acid residue, a d-glutamic acid residue, an alanine residue or absent, Z₃₉ is a serine residue, a d-serine residue, an alanine residue or absent, Z₄₀ is a glutamic acid, a d-glutaminc acid residue, an alanine residue or absent Z₄₁ is a serine residue, a d-serine residue, an alanine residue or absent, Z₄₂ is a serine residue, a d-serine residue, an alanine residue or absent, Z₄₃ is a serine residue, a d-serine residue, an alanine residue or absent, Z₄₄ is a phenylalanine residue, a d-phenylalanine residue, an alanine residue or absent, Z₄₅ is a histidine residue, a d-histidine residue, an alanine residue or absent, Z₄₆ is a serine residue, a d-serine residue, an alanine residue or absent, Z₄₇ is a serine residue, a d-serine residue, an alanine residue or absent, wherein at least one of Z₁-Z₄₇ is absent.
 29. The compound of claim 28, wherein: Z₁ is a glycine residue, Z₂ is an alanine residue, Z₃ is a lysine residue, Z₄ is a phenylalanine residue, Z₅ is a lysine residue, Z₆ is a threonine residue, Z₇ is a serine residue, Z₅ is an alanine residue, Z₉ is a glutamine residue, Z₁₀ is a histidine residue or absent, Z₁₁ is an alanine residue or absent, Z₁₂ is a leucine residue or absent, Z₁₃ is a threonine residue or absent, Z₁₄ is a serine residue or absent, Z₁₅ is a valine residue or absent, Z₁₆ is a serine residue or absent, Z₁₇ is an arginine residue or absent, Z₁₈ is a glycine residue or absent, Z₁₉ is a serine residue or absent, Z₂₀ is a serine residue or absent, Z₂₁ is a leucine residue or absent, Z₂₂ is a lysine residue or absent, Z₂₃ is an isoleucine residue, a serine residue or absent, Z₂₄ is a leucine residue or absent, Z₂₅ is a serine residue or absent, Z₂₆ is a lysine residue or absent, Z₂₇ is a glycine residue or absent, Z₂₈ is a lysine residue or absent, Z₂₉ is an arginine residue or absent, Z₃₀ is a glycine residue or absent, Z₃₁ is a glycine residue or absent, Z₃₂ is a histidine residue or absent, Z₃₃ is a serine residue or absent, Z₃₄ is a serine residue or absent, Z₃₅ is a valine residue or absent, Z₃₆ is a serine residue or absent, Z₃₇ is a threonine residue or absent, Z₃₈ is a glutamic acid residue or absent, Z₃₉ is a serine residue or absent, Z₄₀ is a glutamic acid residue or absent, Z₄₁ is a serine residue or absent, Z₄₂ is a serine residue or absent, Z₄₃ is a serine residue or absent, Z₄₄ is a phenylalanine residue or absent, Z₄₅ is a histidine residue or absent, Z₄₆ is a serine residue or absent, and Z₄₇ is a serine residue or absent.
 30. The compound of claim 28, wherein Z₁ is a glycine residue or absent, Z₂ is an alanine residue or absent, Z₃ is a lysine residue or absent, Z₄ is a phenylalanine residue or absent, Z₅ is a lysine residue or absent, Z₆ is a threonine residue or absent, Z₇ is a serine residue or absent, Z₈ is an alanine residue or absent, Z₉ is a glutamine residue or absent, Z₁₀ is a histidine residue or absent, Z₁₁ is an alanine residue or absent, Z₁₂ is a leucine residue or absent, Z₁₃ is a threonine residue or absent, Z₁₄ is a serine residue or absent, Z₁₅ is a valine residue or absent, Z₁₆ is a serine residue or absent, Z₁₇ is an arginine residue or absent, Z₁₈ is a glycine residue or absent, Z₁₉ is a serine residue or absent, Z₂₀ is a serine residue absent, Z₂₁ is a leucine residue or absent, Z₂₂ is a lysine residue or absent, Z₂₃ is an isoleucine residue, or absent, Z₂₄ is a leucine residue or absent, Z₂₅ is a serine residue or absent, Z₂₆ is a lysine residue or absent, Z₂₇ is a glycine residue or absent, Z₂₈ is a lysine residue or absent, Z₂₉ is an arginine residue or absent, Z₃₀ is a glycine residue or absent, Z₃₁ is a glycine residue or absent, Z₃₂ is a histidine residue or absent, Z₃₃ is a serine residue or absent, Z₃₄ is a serine residue or absent, Z₃₅ is a valine residue or absent, Z₃₆ is a serine residue or absent, Z₃₇ is a threonine residue or absent, Z₃₈ is a glutamic acid residue, Z₃₉ is a serine residue, Z₄₀ is a glutamic acid residue, Z₄₁ is a serine residue, Z₄₂ is a serine residue, Z₄₃ is a serine residue, Z₄₄ is a phenylalanine residue, Z₄₅ is a histidine residue, Z₄₆ is a serine residue, and Z₄₇ is a serine residue.
 31. The compound of claim 28, wherein Z₁ is absent, and 10 consecutive Z₂-Z₄₇ are present wherein: Z₂ is an alanine residue or absent, Z₃ is a lysine residue or absent, Z₄ is a phenylalanine residue or absent, Z₅ is a lysine residue or absent, Z₆ is a threonine residue or absent, Z₇ is a serine residue or absent, Z₈ is an alanine residue or absent, Z₉ is a glutamine residue or absent, Z₁₀ is a histidine residue or absent, Z₁₁ is an alanine residue or absent, Z₁₂ is a leucine residue or absent, Z₁₃ is a threonine residue or absent, Z₁₄ is a serine residue or absent; Z₁₅ is a valine residue or absent, Z₁₆ is a serine residue or absent, Z₁₇ is an arginine residue or absent, Z₁₈ is a glycine residue or absent, Z₁₉ is a serine residue or absent, Z₂₀ is a serine residue absent, Z₂₁ is leucine residue or absent, Z₂₂ is a lysine residue or absent, Z₂₃ is an isoleucine residue, or absent, Z₂₄ is a leucine residue or absent, Z₂₅ is a serine residue or absent, Z₂₆ is a lysine residue or absent, Z₂₇ is a glycine or absent, Z₂₈ is a lysine residue or absent, Z₂₉ is an arginine residue or absent, Z₃₀ is a glycine residue or absent, Z₃₁ is a glycine residue or absent, Z₃₂ is a histidine residue or absent, Z₃₃ is a serine residue or absent, Z₃₄ is a serine residue or absent, Z₃₅ is a valine residue or absent, Z₃₆ is a serine residue or absent, Z₃₇ is a threonine residue or absent, Z₃₈ is a glutamic acid residue, Z₃₉ is a serine residue, Z₄₀ is glutamic acid residue, Z₄₁ is a serine residue, Z₄₂ is a serine residue, Z₄₃ is a serine residue, Z₄₄ is a phenylalanine residue, Z₄₅ is a histidine residue, Z₄₆ is a serine residue, and Z₄₇ is a serine residue.
 32. The compound of claim 28 selected from any one of the compounds 84 and 87-106.
 33. A compound represented by Formula I: T-L-P, or a pharmaceutically acceptable salt thereof, wherein; P is a peptide sequence selected from: SEQ ID NOS: 1-368; L is a linking moiety represented by C(O) and bonded to P at an N terminal nitrogen of an N-terminal amino-acid residue; and T is a lipophilic tether moiety bonded to L.
 34. The compound of claim 33, wherein the C-terminus of SEQ ID NOS. 1-148; is functionalized with NR₁R₂, wherein R₁ and R₂ are each independently H or alkyl.
 35. The compound of claim 33, wherein the C-terminus of SEQ ID NOS 1-148; is functionalized with NH₂.
 36. The compound of claim 33, further comprising a lipophilic tether moiety bonded on the C-terminus of P.
 37. The compound of claim 33, wherein P is selected from SEQ ID NOS: 1-148.
 38. The compound of claim 33, wherein P is selected from SEQ ID NOS: 149-199.
 39. The compound of claim 33, wherein P is selected from SEQ ID NOS: 200-254.
 40. The compound of claim 33, wherein P is selected from SEQ ID NOS: 255-368.
 41. The compound of claim 1, wherein T is an optionally substituted (C₆-C₃₀)alkyl, (C₆-C₃₀)alkenyl, (C₆-C₃₀)alkynyl, wherein 0-3 carbon atoms are replaced with oxygen, sulfur, nitrogen or a combination thereof.
 42. The compound of claim 41, wherein T is selected from the group consisting of: CH₃(CH₂)₁₆, CH₃(CH₂)₁₅, CH₃(CH₂)₁₄, CH₃(CH₂)₁₃, CH₃(CH₂)₁₂, CH₃(CH₂)₁₁) CH₃(CH₂)₁₀, CH₃(CH₂)₉, CH₃(CH₂)₈, CH₃(CH₂)₉OPh-, CH₃(CH₂)₆C═C(CH₂)₆, CH₃ (CH₂)₁₁O(CH₂)₃, and CH₃(CH₂)₉O(CH₂)₂.
 43. The compound of claim 1, wherein T is a fatty acid derivative.
 44. The compound of claim 43, wherein the fatty acid is selected from the group consisting of: butyric acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, myristoleic acid, palmitoleic acid, oleic acid, linoleic acid, α-linolenic acid, arachidonic acid, eicosapentaenoic acid, erucic acid, docosahexaenoic acid.
 45. The compound of claim 1, wherein T is a bile acid derivative.
 46. The compound of claim 45, wherein the bile acid is selected from the group consisting of: lithocholic acid, chenodeoxycholic, acid, deoxycholic acid, cholanic acid, cholic acid, ursocholic acid, ursodeoxycholic acid, isoursodeoxycholic acid, lagodeoxycholic acid, dehydrocholic acid, hyocholic acid, and hyodeoxycholic acid.
 47. The compound of claim 1, wherein T is selected from sterols; progestagens; glucocorticoids; mineralcorticoids; androgens; and estrogens.
 48. The compound of claim 1, wherein TL is selected from: CH₃(CH₂)₁₅—C(O); CH₃(CH₂)₁₃—C(O); CH₃(CH₂)₉—O(CH₂)₂C(O); CH₃(CH₂)₁₀O(CH₂)₂C(O); CH₃(CH₂)₆C—C(CH₂)₆—C(O); LCA-C(O); and CH₃(CH₂)₉OPh-C(O) wherein


49. The compound of claim 1, wherein T is selected from:


50. A method of treating diseases and conditions associated with CXCR4 receptor modulation in a patient in need thereof comprising administering to said patient and effective amount of a compound of claim
 1. 51. The method of claim 50, wherein the disease or condition is selected from: bone marrow transplantation, chemosensitization, cancer, metastatic disease, inflammatory diseases, HIV infection and stem cell-based regenerative medicine.
 52. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier. 